Genetic regulation of preimplantation embryo survival

Genetic regulation of preimplantation embryo survival

06/12/2001 02:49 PM Developmental Biology-V. 52 PS057-04.tex PS057-04.xml APserialsv2(2000/12/19) 4 Genetic Regulation of Preimplantation Embryo...

23MB Sizes 0 Downloads 31 Views

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

4 Genetic Regulation of Preimplantation Embryo Survival Carol M. Warner1 and Carol A. Brenner 2 1

Department of Biology Northeastern University Boston, Massachusetts 02115

2

Gamete and Embryo Laboratory Institute for Reproductive Medicine and Science of Saint Barnabas Medical Center West Orange, New Jersey 07052

I. Introduction II. Preimplantation Development III. Environmental Effects on Preimplantation Embryo Survival A. Culture Media B. Exposure of Embryos to Toxic Substances C. Protection of Embryos by the Zona Pellucida IV. Genetic Effects on Preimplantation Embryo Survival A. Embryonic Genes B. Lethal Mutations C. Mitochondrial Genes D. Genomic Imprinting E. Nuclear Transfer and Reprogramming F. Telomeres and Telomerase V. Genes That Regulate Preimplantation Growth A. Growth Factors B. The Ped Gene C. Genes That Regulate Cell Cycle Processes VI. Genes That Regulate Preimplantation Death VII. Conclusions References

I. Introduction All mammals undergo a period of development between fertilization and implantation that is called the preimplantation period. Embryo survival during this preimplantation period is dependent on both environmental and genetic factors and is crucial for a successful pregnancy. The elucidation of the genes that control Current Topics in Developmental Biology, Vol. 52 C 2001 by Academic Press. All rights of reproduction in any form reserved. Copyright  0070-2153/01 $35.00

151

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

152

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

preimplantation embryo survival is complex. Revolutionary new methods in biology, including whole genome DNA sequence analysis, detection of single nucleotide polymorphisms (SNPs) and mRNA expression with DNA chips and microarrays, cloning of animals by nuclear transfer, and creation of gene knockout mice and embryonic stem cells, should all aid in furthering the understanding of the genetic control of preimplantation embryo survival. The appearance of these new methodologies makes this a particularly timely moment at which to evaluate the status of what is known about the regulation of preimplantation embryo survival and to speculate about what the future might hold. In this review we focus on two species, the mouse and the human, with only occasional references to other species. The reasons are that the mouse is the most thoroughly studied mammalian system with respect to preimplantation development, and that the advent of assisted reproductive technologies (ART), including in vitro fertilization (IVF), has allowed access to spare human embryos for genetic studies. Because of the vast magnitude of this field and the limited space for this review, we apologize to those researchers whose work is not cited. The emphasis of this review is on particular genes that influence the growth and death of preimplantation mouse and human embryos.

II. Preimplantation Development Preimplantation mammalian development is defined as the period between fertilization of the oocyte (egg) and implantation of the embryo into the uterus (Menezo and Renard, 1993; Hogan et al., 1994; Schultz, 1999). During the preimplantation period mammalian embryos undergo a series of cleavage divisions leading to the formation of a blastocyst. Images depicting preimplantation mouse embryo development and preimplantation human embryo development from the fertilized egg to the blastocyst stage are shown in Figs. 1 and 2, respectively. The embryos are surrounded by a porous extracellular coat, the zona pellucida (Wassarman et al., 1999). Cell division in mammalian embryos is somewhat asynchronous after the two-cell stage, but the cleavage stages are referred to as “four cell,” “eight cell,” etc., even though these numbers might not reflect the exact number of cells in a particular embryo. At the 8-cell stage in mice and at approximately the 16-cell stage in humans, the embryos undergo a morphological event called “compaction,” in which the distinction between the blastomeres is lost. Next, a solid ball of cells called the morula is formed, and on further cleavage division, the morula gives rise to the blastocyst. The blastocyst is a fluid-filled, ball-shaped object consisting of two types of cells, an outer layer termed the trophectoderm (TE), and a clump of inner cells called the inner cell mass (ICM) (see Figs. 1E and 2E). Depending on the location of the TE cells with respect to the ICM, the TE cells are defined as polar TE (abutting the ICM) or mural TE (distal to the ICM). The cells of the ICM that

Textures 2.0

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Figure 1 Mouse preimplantation embryos.

06/12/2001

153

Textures 2.0

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Figure 2 Human preimplantation embryos.

06/12/2001

154

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

155

4. Genetic Regulation of Preimplantation Embryo Survival Table I Experimentally Determined Protein, RNA, and DNA Content of Preimplantation Mouse Embryosa

Stage One-cell Two-cell Eight-cell Morula Blastocyst

Hours post-hCG

Protein/embryo (ng)

RNA/embryo (ng)

DNA/embryo (pg)

18 43 71 80 90

28 26 24 21 24

0.55 0.40 0.46 Not reported 1.37

29 41 155 Not reported 439

hCG, Human chorionic gonadotropin. a Protein data from Brinster (1967); RNA and DNA data from Olds et al. (1973).

contact the blastocoelic cavity form the primitive endoderm of the embryos; the other ICM cells form the primitive ectoderm from which the primitive ectodermal and germ cells of the embryos arise. A few primitive ectoderm cells from the ICM also differentiate into some extraembryonic tissues. The rest of the extraembryonic tissues, including the placenta, arise from the TE. There is a polarity to zygotes that sets the stage for development of the ICM and the TE in the blastocyst (Gardner, 1997). The size of mouse embryos, about 100 µm in diameter, and of human embryos, about 155 µm in diameter, does not change during the preimplantation period, which is why the preimplantation cell divisions are called “cleavage divisions.” The cellular portion of mouse embryos is about 70 µm in diameter and the thickness of the zona pellucida is about 15 µm, to give a total diameter of about 100 µm; the cellular portion of human embryos is about 115 µm and the thickness of the zona pellucida is about 20 µm, to give a total diameter of about 155 µm. The protein, RNA, and DNA content of different stages of preimplantation mouse embryos are shown in Table I. Similar experimental data are not available for human

Table II Calculated Estimates of Protein, RNA, and DNA Content of Preimplantation Human Embryos

Stage One-cell Two-cell Eight-cell Morula Blastocyst

Hours post-hCG

Protein/embryo (ng)

RNA/embryo (ng)

DNA/embryo (pg)

18 42 72 96 120

124 115 106 93 106

2.4 1.8 2.0 — 6.1

128 182 691 — 1945

hCG, Human chorionic gonadotropin.

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

156

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner Table III Characteristics of Preimplantation Embryos from a Variety of Mammalian Species

Species

Major ZGAa (cell stage)

Blastocyst formationb (days postfertilization)

Implantationb (days postfertilization)

Mouse Human Rabbit Cow Sheep Pig

2-cell 4-cell 8- to 16-cell 8-cell 8-cell 4-cell

4–5 5–6 3–4 7–8 6–7 5–6

5–6 6–7 6 22 15 13

ZGA, Zygotic genomic activation. a Data from Exley and Warner (1999b). b Data on mouse and human from Hardy (1993); data on rabbit from Davies and Hesseldahl (1971); data on cow, sheep, and pig from Bazer et al. (1993).

embryos. However, on the basis of the relative size of human embryos compared with mouse embryos one can calculate the probable amounts of protein, RNA, and DNA in human embryos. These estimated numbers are shown in Table II. Because of the small quantities of material available from preimplantation mammalian embryos, highly specialized microtechniques are often used in experimental embryo manipulation. The time between fertilization and blastocyst formation varies among species and this is summarized for a variety of species in Table III. After blastocyst formation occurs, a period of blastocyst expansion follows that ends with the “hatching” of the blastocyst from the zona pellucida. For some species, including the mouse and human, implantation occurs directly after hatching, while for other species, such as the pig, there is a period of embryo elongation after hatching and before implantation. Differences in the timing of implantation for a variety of species are also shown in Table III. The final parameter shown in Table III is the time of major zygotic genomic activation (ZGA). The unfertilized oocyte has stores of maternal mRNA that are largely degraded after fertilization. ZGA refers to the time after fertilization at which transcription of new mRNAs from the embryonic genome occurs (Exley and Warner, 1999b).

III. Environmental Effects on Preimplantation Embryo Survival A. Culture Media All phenotypes, including embryo survival, are dependent on both environmental and genetic factors. However, it is often difficult to separate environmental from

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

157

genetic factors in ascertaining parameters involved in embryo survival because the embryos are in the milieu of the maternal oviductal or uterine fluid, depending on their stage of development. A major breakthrough in this area was the development of chemically defined culture media in which mouse embryos could be grown in vitro (Whitten and Biggers, 1968). Despite extensive efforts to improve culture media over the years, rates of in vitro development still do not match up with rates of in vivo development (Biggers, 1998; Loutradis et al., 2000). Moreover, there are changing metabolic requirements for preimplantation embryos during the course of development, so it is probably not possible to design a single ideal culture medium for the entire preimplantation period (Gardner, 1998). It has been shown that certain culture media interfere with normal gene expression. For instance, gene imprinting (preferential expression of paternally inherited vs. maternally inherited genes) is perturbed for the imprinted H19 gene when embryos are grown in certain culture media (Doherty et al., 2000). Another example of the importance of the environment to embryo health and survival is highlighted by cloning experiments in sheep and cattle that are often plagued with a phenomenon called “large offspring syndrome” (Young et al., 1998; Pennisi and Vogel, 2000). The consensus is that the poking and prodding of the embryos during the cloning procedures may be one culprit that leads to large (and often unhealthy) offspring, but the chemical composition of the culture media is also most probably another culprit. In addition, it has been hypothesized that a compromised environment of the embryo during the preimplantation period can lead to health problems later in life, such as cardiovascular disease and high blood pressure (Barker, 1995; Kwong et al., 2000). One solution to the problem of inappropriate culture conditions for preimplantation embryos would be to conduct a complete chemical analysis of the components of the oviductal and uterine fluids throughout the period of preimplantation development. This may be possible with future advances in analytical chemistry that use highly sensitive mass spectrometric. methods

B. Exposure of Embryos to Toxic Substances Embryo survival is directly affected by exposure to toxic substances (Kimmel et al., 1993). For instance, in the mouse, there is a decreased rate of preimplantation development and dose-dependent toxicity on exposure to alcohol (Cebral et al., 1999, 2000), azidothymidine (AZT) (Sieh et al., 1992; Toltzis et al., 1993; C. M. Warner, unpublished data, 2001), ethylene oxide (Polifca et al., 1996), mitomycin C (Nagao et al., 2000), and excess glucose (Moley, 1999). Exposure to excess glucose causes an increase in apoptosis in preimplantation mouse embryos; this is discussed in more detail below. For acetaminophen, different effects on preimplantation development were observed when the embryos were exposed to this compound in vitro compared with in vivo. The embryos exposed in vitro showed depressed embryo development from the morula to the blastocyst stage, but embryos exposed

Textures 2.0

06/12/2001

02:49 PM

158

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

in vivo had no deleterious effects of acetaminophen exposure (Laub et al., 2000). The most likely reason is that the maternal liver is active in eliminating substances, such as acetaminophen, that could potentially harm the developing embryo. Another example of a reported deleterious effect of an exogenous compound on preimplantation mouse embryo development is the finding that exposure of two-cell mouse embryos to active cannabinoids inhibits blastocoel formation, trophoblast proliferation, and hatching from the zona pellucida (Wang et al., 1999). Also, brief exposure of embryos to N-methyl-N-nitrosourea during the preimplantation period can lead to malformations and poor fetal outcome later in the pregnancy (Bossert et al., 1990). Thus, many of the parameters described above, with respect to morphological changes in the embryo during the preimplantation period, are subject to modification by toxic substances in the environment, and the effects of these toxic substances may occur long after the period of preimplantation exposure is over. Interestingly, there is some indication that substances toxic to mouse embryos are not necessarily the same as substances toxic to human embryos. For instance, one study has shown that endotoxins are not deleterious to mouse embryos but cause embryo fragmentation and low pregnancy rates in humans undergoing IVF (Dumoulin et al., 1991). To increase the viability of human embryos cultured in vitro, coculture with fetal bovine uterine fibroblasts or bovine oviductal epithelial cells is often used. The coculture cells may metabolize toxins, thus reducing their levels, and may also provide beneficial growth factors for the embryos (Wiemer et al., 1998). Coculture results in an increased rate of cleavage, a significantly reduced rate of embryo fragmentation, and higher implantation and pregnancy rates. In addition, it is thought that the origins, effects, and control of air pollution in laboratories used for human embryo culture must be routinely assayed for aldehydes (Hall et al., 1998).

C. Protection of Embryos by the Zona Pellucida A unique feature of preimplantation embryos is the presence of the zona pellucida. The zona pellucida is responsible for species specificity of fertilization and is a secondary site to the block of polyspermy (Wassarman and Mortillo, 1991; Yanagimachi, 1994). One might initially think that the zona pellucida would provide some protection from toxic chemicals, but this is apparently not the case. The zona pellucida is composed of about 80% protein (three unique proteins called ZP1, ZP2, and ZP3) and 20% carbohydrate. It is a porous structure and is permeable to most small molecules (Turner and Horobin, 1997), to large proteins such as immunoglobulins (Sellens and Jenkinson, 1975), and even to small viruses (Wassarman, 1988). It is particularly intriguing that antibodies can cross the zona pellucida because this raises the question of how embryos are protected from cytolysis by

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

4. Genetic Regulation of Preimplantation Embryo Survival

159

autoantibodies that could potentially lyse the embryos in the presence of complement. We have shown that preimplantation mouse embryos express mRNA for FcRn (Warner and Paschetto, 2000). It is unknown whether FcRn protein is also expressed by the embryos. If FcRn protein is found to be expressed by preimplantation embryos, it is possible that any antibodies in the oviductal or uterine fluid could be bound to the embryos by the Fc region of the antibody, making the initiation of the complement cascade impossible. The whole area of protection of preimplantation embryos from complementmediated lysis is an interesting one that deserves further investigation. One study has shown that knockout of a complement regulatory gene in mice, Crry, results in fetal death midgestation (Xu et al., 2000), but no studies have yet been reported on the expression of the Crry gene in preimplantation embryos. In humans, it has been reported that complement-binding proteins are expressed on blastocysts (Taylor and Johnson, 1996), but it remains to be determined how human embryos escape complement-mediated lysis. One area that has received little attention is the possible role of the zona pellucida in protecting the embryo from attack by cells of the maternal immune system. A diagram depicting three possible types of maternal killer cells, cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and macrophages (M), and their potential interaction with embryonic target molecules, is shown in Fig. 3 (see color insert). It has been demonstrated that killing of preimplantation mouse embryos by CTLs directed to major histocompatibility complex (MHC) class Ia proteins is possible only after removal of the zona pellucida (Ewoldsen et al., 1987). The role of the zona pellucida in NK cell- and macrophage-mediated killing of preimplantation embryos is unknown. Future research aimed at defining a topological map of the proteins on the cell surface of preimplantation embryos should lead to an eventual understanding of how preimplantation embryos escape killing by the maternal immune system.

IV. Genetic Effects on Preimplantation Embryo Survival Almost any gene that is expressed in preimplantation embryos could play a role in regulating their survival. For the mouse the expression of hundreds of genes has been assayed, but because of limited availability of human embryos, the number of genes whose expression has been assayed is still quite low. The presence of genes, including particular alleles, mutations, and SNPs, can be detected by using polymerase chain reaction (PCR), or by using DNA chips or microarrays. Likewise, the presence of mRNAs for particular genes can be assayed by using reverse transcriptase (RT)-PCR, or by using DNA chips or microarrays. It should be noted that the presence of mRNA for a particular protein does not guarantee that the protein will be expressed, although the absence of mRNA for a particular protein does indicate that new protein cannot possibly be synthesized. Moreover, several

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

160

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

articles have shown that there is little correlation of mRNA levels with protein levels in various types of cells (Anderson and Seilhamer, 1997; Gygi et al., 1999). Therefore, as a general principle, it is crucial to measure protein levels as well as mRNA levels to understand protein expression and function in preimplantation embryos. In this section we review the expression, in preimplantation mouse and human embryos, of a select set of genes that seem particularly relevant to development and/or have particular significance with respect to embryo survival in the ART clinic. This section includes those nuclear and mitochondrial genes that affect many aspects of embryo development and survival, but excludes those genes that regulate growth and death. These latter two types of genes will be discussed in subsequent sections.

A. Embryonic Genes Genetic effects on preimplantation embryo survival may be of maternal or embryonic origin. Of particular interest to this review are genes that are expressed by the embryos themselves independent of the maternal environment. To this end, DNA chip and microarray technology should allow the complete description of all genes that are expressed during each stage of development. The first study of this type has been reported by Ko et al. (2000). They found that preimplantation mouse embryos expressed mRNAs for more than 9000 genes and that the pattern of gene expression changed throughout development. These results confirmed the idea that there is a genetically programmed sequence of events in which different genes are turned on and off during the preimplantation period. When the entire mouse genome has been sequenced (expected by the time this article is published), it will be possible to screen all of the genes (estimated at 30 –100,000) to determine which ones are transcribed throughout preimplantation development. Since the complete human DNA genomic sequence has been reported, this is already possible with human embryos, and preliminary studies along these lines have been initiated in several laboratories (Brenner and Cohen, 2000). The analysis of the gene expression data to be generated is quite complex and will need sophisticated approaches from the field of bioinformatics to yield information that is biologically useful. A major challenge will be to move from genomics to proteomics to identify functions for each of the proteins that arises from mRNA transcribed during the preimplantation period of development. Simultaneous with the global approach of the genomics/proteomics revolution, studies of individual genes that affect preimplantation embryo survival are being conducted by a number of laboratories. As described previously, there are several morphological events during the preimplantation period of development that are candidates for genes that mediate preimplantation survival. These can be broken down into genes that regulate ZGA, genes that regulate compaction, genes that regulate blastocyst formation, and genes that regulate blastocyst elongation. The

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

4. Genetic Regulation of Preimplantation Embryo Survival

APserialsv2(2000/12/19)

161

last category of genes is not discussed in detail since neither mouse nor human preimplantation embryos undergo an elongation phase before implantation. However, it is noteworthy that a study of gene expression during elongation of the preimplantation pig embryo has been published (Wilson et al., 2000). Examples of genes that influence ZGA, compaction, and blastocyst formation are given in the next sections. 1. Genes That Influence Zygotic Genomic Activation As shown in Table III and mentioned previously, the time of ZGA varies among species. In the mouse, a limited amount of transcription occurs in zygotes, but the major onset of ZGA is at the two-cell stage. Several genes that are involved in mouse ZGA have been described, including eIF-1A and transcription-requiring complex (TRC) (Schultz et al., 1999), as well as GAGA box-binding factor and Sp1 (Bavilacqua et al., 2000). ZGA is related to nuclear reprogramming, which is particularly relevant to cloning from adult cells, a subject discussed later in this article. In human preimplantation embryos a dramatic reprogramming of gene expression occurs from the four- to the eight-cell stage (Braude et al., 1988). More precise estimates of the timing of ZGA depend on the detection of de novo transcripts from the zygotic genome, which varies according to the sensitivity of the techniques used and the specific genes analyzed. Braude et al. (1988) have hypothesized that reprogramming of gene expression in the human preimplantation embryo mostly likely involves DNA replication and chromatin remodeling. Although the gene expression of eIF-1A and TRC has not been assayed in human embryos, paternal transcripts for the Y-linked genes ZFY and SRY, as well as the myotonic dystrophy-associated protein kinase gene DK, have been detected as early as the late pronuclear, one-cell stage (Pergament and Fiddler, 1998). Furthermore, since the high incidence of human embryonic arrest coincides with the transition from maternal to embryonic regulation of development, it has been proposed that the failure of ZGA is responsible. 2. Genes That Influence Compaction In the mouse, several genes have been described that influence compaction. Compaction is basically a cell adhesion event that is regulated by the expression of a series of cell surface proteins including E-cadherin (also known as uvomorulin) (Kemler et al., 1977; Vestweber et al., 1985). Other proteins involved in the adhesion process are the catenins and the actin cytoskeleton and the interaction of these proteins is now well documented (Nieset et al., 1997). Compaction is known to be controlled at the posttranslational level since exposure to protein synthesis inhibitors does not impede compaction (Kidder and McLachlin, 1985; Levy et al., 1986). It is still not clear exactly what the posttranslational modifications are that control compaction, although it is thought that phosphorylation events mediated by

Textures 2.0

06/12/2001

02:49 PM

162

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

phosphatases and/or kinases are largely responsible (Goval and Alexandre, 2000). One of these, protein kinase C (PKC), is definitely involved in the regulation of compaction. It has been shown that seven isotypes of PKC are expressed by preimplantation mouse embryos, and that a key redistribution of the PKC isotypes occurs at the time of compaction (Pauken and Capco, 2000). Thus, quite a bit is known about the genetic regulation of compaction in preimplantation mouse embryos, but complete elucidation of all the genes involved is yet to come. Compaction of cleaving human preimplantation embryos changes them from a collection of individual cells into a solid mass with indistinguishable cell membranes. As in the mouse, compaction is due to the formation of tight junctions causing the blastomeres to become closely apposed. The positioning increases the extent of contact between the blastomeres that is essential for subsequent development. In humans this usually occurs at about the 8- to 16-cell stage (Nikas et al., 1996). Although compaction has been observed at earlier stages, it is not known whether this represents a normal occurrence. When compaction takes place, the cells lose their totipotency as the result of cell–cell interactions and it is believed that the onset of compaction marks the beginning of major ZGA in human embryos. During compaction a number of cellular changes occur within the embryo that ensure the subsequent establishment of the trophectoderm. These changes include the formation of tight junctions, gap junctions, and cytoskeletal connections and reorganization between blastomeres. Prior to implantation, the human embryo expresses connexin-containing gap junctions (Hardy et al., 1996). Desmosomes appear between outer cells prior to cavitation and are retained in the trophectoderm of the late blastocyst. Other relevant cell adhesion molecules active during compaction in human preimplantation embryos still remain to be elucidated. 3. Genes That Influence Blastocyst Formation After compaction, the next major morphological landmark in preimplantation development is blastocyst formation. It is generally agreed that the major control of blastocyst formation is by the plasma membrane sodium pump, Na+/K+-ATPase (Watson, 1992). Studies of bovine embryos have shown that disruption of Na+/K+ATPase gene expression by antisense oligonucleotides abolishes blastocyst formation (Watson et al., 1999). In the mouse there are several isozymes of Na+/K+ATPase, and similar to the observation reported above on the role of different isozymes of PKC in compaction, there are probably differential roles for as many as six isozymes of Na+/K+-ATPase in blastocyst formation (MacPhee et al., 2000). There are, undoubtedly, multiple genes other than Na+/K+-ATPase that are involved in blastocyst formation. For instance, it has been reported that there is an association between insulin-like growth factor (IGF-I) expression and blastocyst formation in mouse embryos (Kowalik et al., 1999). In humans, IGF-I not only enhances growth of preimplantation embryos, but also reduces apoptotic cell death (Spanos et al., 2000). Another report has suggested that the splicing factor SRp20

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

163

is involved in mouse blastocyst formation (Jumaa et al., 1999). In this study the SRp20 gene was knocked out by using the Cre–loxP system and it was found that development in the resulting mice was blocked at the morula stage. Tight junction assembly during blastocyst formation is also under genetic control in the mouse (Sheth et al., 1997, 2000). In humans, approximately 24 h after the morula has formed and compaction has taken place, the intercellular spaces begin to enlarge to create the central fluid-filled cavity, the blastocoel. As in the mouse, the human blastocyst consists of ICM and TE cells (Figs. 1 and 2). Expanded human blastocysts have a total cell number of 60 cells on day 5, which increases to 80 and 125 on days 6 and 7, respectively (Gardner and Schoolcraft, 1999). (This compares with about 32 cells in day 4 mouse blastocysts.) The proportion of ICM cells in human blastocysts ranges from 33 to 50% between days 5 and 7. It has also been observed that although the human blastocyst expands readily in vitro, about 20% of such blastocysts have hatching problems. Rescue of these blastocysts can be accomplished by assistedhatching (AHA), using acidic Tyrode’s solution to create a gap in the zona pellucida before intrauterine transfer (Cohen et al., 1991). The AHA technique is also used to save blastocysts trapped in overtly thick zonae pellucidae. Selective embryo hatching protocols in the IVF clinic have promoted both higher implantation rates and pregnancy outcomes for infertile women. There are multiple genes that affect human blastocyst development, including genes that encode proteins that can be characterized as growth factors and their receptors, gene regulators, and transcription factors. Some examples are the transcription regulators OCT4 and OCT6 (Abdel-Rahman et al., 1995; Ben-Shushan et al., 1998; Hansis et al., 2000), a cell surface glycoprotein CD44, insulin growth factors and their receptors, heparin-binding epidermal growth factor (HB-EGF) and its associated EGF receptor, leukemia inhibitory factor (LIF) and its receptor, as well as matrix metalloproteinases (MMPs), which are crucial proteases for the implantation process (Brenner et al., 1989; Pergament and Fiddler, 1998). Implantation rates, although increasing in the IVF clinic, range from 5 to 30% and repeated implantation failures occur commonly in clinical practices. One suggestion to improve pregnancy rates has been to transfer blastocysts on day 5, rather than eight-cell embryos on day 3, to recipient mothers. In this way any embryos with aberrant gene expression leading to embryonic arrest would be eliminated and the resulting blastocysts would presumably have a better chance of leading to a successful pregnancy. Thus, a full understanding of the genes that regulate blastocyst formation in human embryos has potential clinical importance.

B. Lethal Mutations Mutations that arrest preimplantation development are scarce compared with mutations that affect postimplantation development (Magnuson et al., 1993). The

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

164

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

reasons for this are not clear, but it is possible that stores of maternal mRNAs and proteins in the oocyte can provide a boost that allows embryos to develop to the blastocyst stage in spite of potentially lethal mutations. Another possibility is that major genes regulating preimplantation development have other genes with redundant functions capable of substituting for them, so that a point mutation in one particular gene would not necessarily be lethal during the preimplantation period. A few preimplantation embryonic lethal mutations that have been described in the mouse are t12 (located in the T/t complex on chromosome 17), which is lethal at the morula stage (Cheng et al., 1983); pin (located in the albino complex on chromosome 7), which arrests cell division some time between the two- and six-cell stages and causes embryo death 1–2 days later (Magnuson et al., 1993); and mpg or dist1 (located near the α-globin complex on chromosome 11), which causes abnormal development of both the ICM and TE in blastocysts, leading to periimplantation death (Hendrey et al., 1995). A gene encoding a zinc finger transcription factor, Wt1, has been found to have an indirect effect on preimplantation embryo survival by controlling the oviductal environment in conjunction with a modifier oviductal protein that has not yet been identified (Kreidberg et al., 1999). Another gene, Traube (Trb), halts mouse preimplantation development at the compacted morula stage, presumably by interfering with the synthesis of ribosomes (Thomas et al., 2000). So far, in human preimplantation embryos no lethal mutations have been described.

C. Mitochondrial Genes Cellular genes are found not only in the nucleus, but also in cytoplasmic mitochondria. It has been ascertained, using highly sensitive quantitative PCR techniques, that the mouse oocyte contains a mean copy number of about 150,000 mitochondria compared with about 300,000 in the human oocyte (Steuerwald et al., 2000a). Thus, there is a significant amount of mitochondrial DNA (mtDNA) in oocytes and embryos that may contribute to genetic regulation of preimplantation embryo survival. 1. Mitochondrial Mutations There are now more than 150 known mtDNA rearrangements, including deletions, insertions, and duplications (Wallace, 1993). Such mutations in mtDNA are responsible for a number of catastrophic neuromuscular diseases, such as Kearns– Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), and Pearson’s syndrome. Mitochondrial DNA rearrangements have been shown to accumulate with age, and prevalently appear in postmitotic, nondividing tissues (Cortopassi and Arnheim, 1990). When aging tissues accumulate mtDNA rearrangements, and it reaches a significant threshold level, a reduction in the

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

165

efficiency of oxidative phosphorylation occurs. Since the oocyte is a nondividing tissue, which may be subject to meiotic arrest in the ovary for up to 50 years, there must be sufficient copies of the mitochondrial genome to allow the mammalian preimplantation embryo to develop and implant. It is postulated that mitochondrial replication occurs initially during oocyte maturation and then not again until after the egg cylinder stage. Therefore a high frequency of abnormal mitochondria in the oocyte could reduce the number of functional mitochondria leading to embryonic arrest, failed implantation, or mitochondrial disease. In the future, mice carrying mtDNA with pathogenic mutations may provide a system with which to study how the mutant mtDNAs are transmitted and distributed in tissues, resulting in expression of mitochondrial diseases. Mouse cells without mitochondria have been isolated and utilized to trap mtDNAs with somatic mutations (cybrids). Mice can now be generated to model mtDNA disease by electrofusion of fertilized mouse eggs with enucleated cybrids (Inoue et al., 2000). These mice should be useful for studying the precise mechanisms of formation, transmission, and pathogenic expression of duplicated mtDNA and the variation of mtDNA in specific tissues and thus could be models of mtDNA-based diseases. Multiple laboratories have detected a particular mtDNA mutation called the “common deletion,” mtDNA4977, in human oocytes (Chen et al., 1995; Keefe et al., 1995; Brenner et al., 1998; Barritt et al., 1999). The mtDNA4977 mutation can be detected at a frequency of 30 to 50% in human oocytes. Although there is no age-related accumulation of this mutation, there is a significant reduction of mtDNA4977 detected in embryos compared with oocytes (Brenner et al., 1998; Barritt et al., 1999). These findings suggest that a selection mechanism of some type may be working on the oocyte and early preimplantation embryo to reduce or eliminate the inheritance of mitochondrial mutations. In addition, 23 novel mtDNA rearrangements have been identified in human oocytes and embryos (Barritt et al., 1999). Using a nested PCR strategy, 51% of human oocytes and 32% of embryos exhibited mtDNA rearrangements. Multiple rearrangements were detected in 31% of oocytes and 14% of embryos. Thus, a significant reduction in both mtDNA rearrangements and multiple mtDNA rearrangements is found in embryos compared with oocytes. A mtDNA point mutation was discovered that is predominantly present in oocytes from women of advanced age (Barritt et al., 2000a,b). Interestingly, this mtDNA mutation affects the mitochondrial control region responsible for transcription and replication regulation. This mutation represents a single base pair transversion of a thymine (T) to guanine (G) at base pair 414 (T414G) in the mitochondrial genome. In women <37 years of age the frequency of this oocyte mutation was 4% compared with 40% in women older than 37 years of age. The link between mitochondrial mutations, functional impairment of the aging oocyte, and the regulation of mitochondrial replication still remains an unsolved mystery. An interesting proposition is that it should be possible to cure mitochondrial disease by nuclear transfer methods similar to cloning methods discussed below.

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

166

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

2. Cytoplasmic Transplantation Reproductive biologists in IVF clinics have utilized cloning manipulations and techniques to solve many different problems. Transplantation of ooplasm from healthy donor oocytes into oocytes from patients with recurrent implantation failure after ART has led to the birth of healthy babies (Cohen et al., 1998, 1999). The volume of ooplasm transferred, 5–15% of the total ooplasm volume, almost certainly involves the transfer of mitochondria as well as mRNAs, proteins, and other factors. It is not known precisely how ooplasmic transfer affects the physiology of the early human embryo, but it appears that the introduction of a small amount of ooplasm from a donor oocyte may correct certain as yet unspecified ooplasm deficiencies. The clinical experience gained so far supports the idea that the procedure may be useful when conventional ART has repeatedly and consistently failed and when cytoplasmic deficiency of the oocytes is the suspected cause of poor embryo viability. 3. Mitochondrial DNA Heteroplasmy The infusion of mitochondria from a different source may lead to heteroplasmy, that is, the presence of more than one population of mtDNA in a single cell, and the heteroplasmy may persist if the transferred mitochondria survive and replicate throughout embryonic and fetal development. By examining mtDNA from the donor and recipient it is possible to distinguish differences in the mtDNA hypervariable region or the mtDNA fingerprint. Ooplasmic transfer can result in sustained mtDNA heteroplasmy representing both donor and recipient. This was demonstrated by mtDNA fingerprinting of embryos, amniocytes, fetal placenta, and cord blood. These results show that the donor-derived mitochondrial population persists after ooplasmic transfer and may be replicated during fetal development (Brenner et al., 2000). In addition, two mtDNA populations have been found in blood samples from healthy 1-year-old children resulting from ooplasmic transplantation (Barritt et al., 2001). These mtDNA fingerprints demonstrate that the transferred mitochondria can be replicated and maintained in the offspring, without potentially altering mitochondrial function. However, the mechanisms of regulation of the donor’s mitochondrial population in the presence of the recipient’s mitochondrial and nuclear genomes are unknown. These heteroplasmic children will be monitored for the foreseeable future to determine whether the heteroplasmy persists throughout life.

D. Genomic Imprinting Genomic imprinting is the epigenetic mechanism that distinguishes whether genes that are inherited from the maternal versus the paternal genome result in parentspecific gene expression. Genomic imprinting is important in the development and

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

167

survival of mammalian embryos. Genomic imprinting is established according to specific markers that are imposed on the genome during gametogenesis; the allelespecific gene expression is then maintained throughout embryogenesis and is an absolute prerequisite for normal development. The pioneering work of McGrath and Solter (1984) and Surani et al. (1984) enabled researchers to reject lack of a cytoplasmic component from the fertilizing male gamete or homozygosity for recessive lethal alleles as explanations for the abnormal development of uniparental haploid and diploid murine embryos, in favor of parental nonequivalence (i.e., genomic imprinting). In these experiments, nuclear transplantation was used to create embryos with differing parental contributions from inbred mice. In common with haploid parthenotes activated by fertilization with a spermatozoon, uniparental diploid gynogenotes (two maternal nuclei) and androgenotes (two paternal nuclei) also developed to the blastocyst stage but no further. These and other experiments confirmed that the parental genetic contributions were somehow imprinted, distinguishing paternal and maternal components. Imprinting of a parental allele is established during gametogenesis and is intimately associated with the methylation of cytidines located within dinucleotide CG repeating sequences, commonly referred to as CpG islands, which lie outside the coding regions of the gene. We now understand that the paternal genome is more important in the development of extraembryonic tissues, whereas the maternal genome is more closely associated with postimplantation embryonic development. It is thought that there are more than 30 genes that are marked during sperm and egg formation that are selectively switched off in the embryo. Understanding the molecular basis for the parental specific expression of Igf 2 is of long-standing interest in the field of imprinting. Igf 2 is part of a cluster of imprinted genes whose organization is well conserved in mice and humans. The paternal-specific Igf 2 gene and its neighbor, the maternal-specific H19 gene, are coregulated since they share enhancers. Dissecting monoallelic expression pathways will therefore contribute toward an understanding of normal gene regulation and of the molecular basis for diseases associated with disregulation of the imprinted loci.

E. Nuclear Transfer and Reprogramming It has become possible to make exact genetic copies (clones) of sheep, cows, goats, monkeys, and mice. It is also possible to utilize techniques such as cytoplasmic and nuclear transplantation in human reproduction. With the development of these new technologies, patterns of gene expression may be examined as well as manipulated. The pattern of gene expression in adult cells is different from that in embryonic cells. Some genes are expressed in adult cells but not in embryonic cells and vice versa. When embryos are analyzed a few hours after the transfer of an adult cell nucleus to an enucleated metaphase II egg, the pattern of gene

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

168

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

expression cannot be distinguished from that in embryos grown from normally fertilized eggs. This means that the egg cytoplasm causes a dramatic switch in gene expression in the transferred nucleus in only a few hours. This switch is called nuclear reprogramming. 1. Nuclear Transfer and Cloning In mammals, normal fertilization begins with the union of the egg and the sperm. The unfertilized oocyte is stopped at metaphase II until the sperm can provide an activation signal that triggers the resumption and the completion of cell division. Nuclear transfer subverts fertilization by replacing the female genetic material from the unfertilized egg with the nucleus from a different somatic or embryonic cell. This was first done successfully on frogs. Nuclear transplantation in mammals has proved more difficult than in frogs. Although it is easier to clone mammals from embryonic or fetal cells, it is now possible to use adult nuclei for the cloning procedure. The cloning of the first mammal from an adult cell, Dolly the sheep, has been followed by successful cloning from an adult cell of cows, mice, and pigs (reviewed in Gurdon and Colman, 1999; Pennisi and Vogel, 2000). 2. Gene Reprogramming Reprogramming normal developmental genes after nuclear transplantation requires approximately 30 genes, which are actively expressed by both the sperm and the oocyte during meiotic maturation. These genes are switched off in the embryo until after ZGA. Imprinted genes are unlikely to be reprogrammed by nuclear transfer because if they were, the embryos would not survive. Another focus of reprogramming is the inactivation of one X chromosome in female mammals (Clerc and Avner, 2000; Eggan et al., 2000). During early development of female mammals, one of the two X chromosomes is randomly inactivated in those tissues contributing to the fetus. Gene reprogramming in mammals seems to occur on the same genes active before nuclear transfer, and does not require the formation of new DNA (Surani, 1998). Key molecules found in the egg, such as telomerase and embryo-specific histones, may be involved in the regulation of reprogramming. 3. Nuclear Transfer at the Germinal Vesicle Stage Nuclear transfer may be used for other purposes than cloning. It may be possible to use transfer of nuclei to germinal vesicle (GV) stage oocytes to reduce the incidence of aneuploidy. The proper segregation of chromosomes is a fundamental prerequisite for the orderly completion of cell division. Inappropriate chromosome separation can result in the production of aneuploid cells and abnormal gametes. While aneuploidy in somatic cells is likely responsible for the development of various cancers, the incidence of aneuploidy in gametes contributes to birth defects

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

169

and pregnancy loss. It is now well established that nondisjunction of bivalent chromosomes during oogenesis, and therefore chromosomal abnormalities, increases significantly with advancing maternal age. The risk of conceiving a chromosomally abnormal fetus during IVF increases from 6.8% for women 35–39 years old to ∼50% in women 45 years of age or older (Liu, et al., 1999; Takeuchi et al., 1999; Zhang et al., 1999). However, it is not known what molecular mechanisms orchestrate chromosome distribution during human oocyte maturation (Steuerwald et al., 2001). Studies have explored whether nuclear transplantation at the GV stage can reverse the effects of aneuploidy (Liu et al., 1999). A GV is removed with a small amount of cytoplasm from an older woman and transferred into an enucleated oocyte from a young woman. Such reconstituted oocytes are placed in culture and allowed to mature so that the extruded first polar bodies can be processed for chromosomal analysis. Many laboratories believe that a complete haploid set of chromosomes can be obtained from the first polar body. Although more extensive research is necessary before GV transfer is used as a therapeutic technique for rescuing genomes from the maternal age-related increase in chromosomal nondisjunction during the first meiotic division in human oocytes, this technique seems promising. However, if the rescue is to be applied to reconstructed mammalian oocytes, they must be capable of fertilization and subsequent embryonic growth. The reprogramming of development genes in the mouse and human oocyte and embryo must be examined to ensure normal human development before this technique can be safely and ethically implemented.

F. Telomeres and Telomerase One of the more intriguing questions in the area of biology is whether mechanisms are already programmed in our genes to determine our life span. Is such a genetic program already determined at birth? Or even prior to birth in the oocyte itself? It is now believed that telomere shortening is a major event in biological aging. Telomeres are repeats of DNA protecting the stability of chromosomes and are essential for chromosome end maintenance. The ribonucleoprotein enzyme that adds these DNA repeats to the ends or tails of the chromosomes is called telomerase. The telomerase catalytic subunit (TCS) is structurally related to reverse transcriptase and thus represents the first member of this family with essential cellular function (Nakamura et al., 1997). Interestingly, telomerase activity is high in germ, embryonic, and cancer cells. All of these are considered telomerase positive. The enzyme is missing in telomerase-negative cells, such as most somatic cells. Immortal cancer cells divide uncontrollably and are telomerase positive. The mechanisms that convert somatic cells to cancer cells are unknown, but may well involve telomerase reactivation. Reactivation of telomerase results in the unscheduled additions of TTAGGG repeats that normally cap human chromosome ends. Cells with elongated telomeres show a spectacular alteration in their growth potential.

Textures 2.0

06/12/2001

02:49 PM

170

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

It is now evident that human oocytes and embryos have high levels of telomerase. The oocyte is the most likely place for the setting of the telomeric clock, since telomeres should be added to the chromosomes prior to fertilization and before the onset of ZGA and blastocyst formation. Logically, mammalian spermatozoa and oocytes should have the longest telomeres to ensure the transmission of full-length chromosomes to the progeny (Kozik et al., 1998). Human oocytes and embryos indeed express the human telomerase catalytic subunit (hTCS). Surprisingly, multiple transcripts of hTCS were also found at different meiotic stages and in embryos (Brenner et al., 1999). Potentially normal donated oocytes did not reveal any alternately spliced variants compared with developmentally abnormal human oocytes and embryos. In early human development the expression of the enzyme may have at least two regulatory mechanisms controlling the activity of telomerase: transcriptional control of the hTCS gene and alternate splicing of its transcripts. Clearly differing telomerase activity in individual mammalian oocytes and embryos may serve as a marker for embryonic health and may even predict life span. The correlation between telomerase activity, telomere length, and cellular replicative capacity mechanisms in oocytes and embryos remains to be fully explored and understood. When researchers announced in 1997 that they had cloned the sheep, Dolly, many scientists asked the question: Are her cells older than she is? Dolly was cloned from an adult cell and everyone wondered whether her own cells would show some of the hallmarks of an older animal. It transpired that Dolly’s telomeres were shorter than normal (Shiels et al., 1999), and because telomeres normally shrink with age, this was a disturbing sign that her cellular clock had not been reset. Mice have also been cloned by nuclear transfer into enucleated oocytes and bred for six generations. Successive generations of these mice showed no signs of premature aging. There was also no evidence of shortening of the telomeres, and in fact there apparently was a slight increase in telomere length (Wakayama et al., 2000). In cattle cloning, transferred nuclei from nearly 100 cultured cells into enucleated eggs eventually produced six cattle. When the blood cells from the young cattle were analyzed, it was found that the calves’ telomeres were at least as long as the telomeres of normal cattle the same age and in some cases even longer than the telomeres of the normal cattle (Lanza et al., 2000). Nuclear transfer from adult somatic cells has produced cloned pigs; however, at this time their telomere length has not been reported (Polejaeva et al., 2000). Thus, telomere length after cloning seems to vary among species and may have an impact on life span.

V. Genes That Regulate Preimplantation Growth Growth during the preimplantation period is one of the most important parameters involved in the regulation of embryo survival. An increased number of cells in the ICM of blastocysts is associated with a greater chance of subsequent fetal survival (Tam, 1988; Brison and Schultz, 1996; Lane and Gardner, 1997; Van Soom

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

171

et al., 1997; Chan et al., 2000), and growth during the preimplantation period is important for synchronization of the embryo with the maternal reproductive tract so that successful implantation can occur (Rogers and Leeton, 2000). Moreover, as pointed out previously, slow growth during the preimplantation period has been shown to be associated with impaired cardiovascular function and high blood pressure later in life (Barker, 1995; Kwong et al., 2000). A. Growth Factors Growth factor receptors are present on preimplantation embryos (Kaye, 1997). The sources of the growth factors that could potentially interact with these growth factor receptors are from the environment, the mother, or the embryos themselves. The latter two sources of growth factors are referred to as paracrine and autocrine, respectively. A diagram of the possible interactions of growth factors with preimplantation embryos is shown in Fig. 4 (see color insert). Effects of various exogenous substances, such as vitamins, oxygen, and lactate, on preimplantation growth have been reported (McKiernan and Bavister, 2000; Trimarchi et al., 2000a,b; Lane and Gardner, 2000). It should be noted that there is no requirement for exogenous growth factors in media used to culture preimplantation embryos in vitro in order to obtain live offspring. However, the embryos themselves produce autocrine growth factors that are required for survival (Lane and Gardner, 1992). Quite a number of studies have appeared defining growth factors produced by preimplantation embryos. These autocrine growth factors include interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 10 (IL-10), colony-stimulating factor (CSF), leukemia inhibitory factor (LIF), transforming growth factor (TGF), epidermal growth factor (EGF), interferon γ (IFN-γ ), gonadotrophin releasing hormone (GnRH), vascular endothelial growth factor (VEGF) (reviewed in Krussel et al., 2000), as well as platelet-activating factor (PAF) (O’Neill, 1998; Emerson et al., 2000), early pregnancy factor (EPF) (Athanasas-Platsis et al., 2000), and acrogranin (Diaz-Cueto et al., 2000). This list will undoubtedly be expanded as the genomics/proteomics revolution proceeds. B. The Ped Gene 1. The Mouse Ped Gene One particularly interesting gene that regulates preimplantation embryonic growth is the Ped gene discovered in our laboratory (Verbanac and Warner, 1981). The properties of the Ped gene have been reviewed by ourselves (Warner et al., 1998a–c) and by others (Fernandez et al., 1999; Gill, 1999). We discovered the Ped gene when we observed that the rate of preimplantation development varied among inbred strains of mice. Although a few other workers had reported apparent genetic differences in the rate of development of preimplantation mouse embryos (Whitten and Dagg, 1962; McLaren and Bowman, 1973; Titenko, 1977), our key

Textures 2.0

06/12/2001

02:49 PM

172

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

observation was that this difference was correlated with the major histocompatibility complex (MHC) haplotype. This led us to propose that there is a gene, Ped (Preimplantation embryo development), in the MHC that influences the rate of cleavage division of early embryos. We defined two functional alleles of the Ped gene, fast and slow, on the basis of the number of cells per embryo at 89 h after human chorionic gonadotropin (hCG) injection (Verbanac and Warner, 1981; Goldbard et al., 1982b), and showed that the fast Ped allele is dominant ( Goldbard et al., 1982a). We also showed that fast and slow development of mouse embryos is maintained in vitro independent of the maternal uterine environment (Brownell and Warner, 1988). Thus, fast and slow development of preimplantation mouse embryos is an intrinsic genetic property of the embryos themselves. In our next set of studies we located the Ped gene to the Q region of the mouse MHC (Warner et al., 1987, 1988, 1991). We were then able to show that Qa-2 protein, the product of two almost identical (one nucleotide difference) Q region genes, Q7 and Q9, was responsible for the Ped gene phenotype (Xu et al., 1994; Wu et al., 1999). Those embryos that express Qa-2 protein cleave at a fast rate whereas those embryos that are missing Qa-2 protein cleave at a slow rate. Embryos missing Qa-2 protein have a deletion of both the Q7 and Q9 genes. Figure 5 (see color insert) shows images of embryos with the Ped fast and Ped slow alleles and also shows that Qa-2 is present on the cell surface of Ped fast embryos, but missing from the surface of Ped slow embryos. It is noteworthy that Qa-2 present on the embryos is below the level of detectability by immunofluorescence, but can be detected by the highly sensitive method of Immuno-PCR (McElhinny and Warner, 1997; Ke and Warner, 2000). The mystery is to determine how a protein on the cell surface can transmit a signal to the embryos to cleave at a faster rate than those embryos that are missing the protein. There are additional functions of the Ped gene beyond the preimplantation period of development. This observation complements many of the studies cited above, in which it was pointed out that rate of growth during the preimplantation period affects health later in life. We have shown that survival to birth, birth weight, and weaning weight are all influenced by the Ped gene (Warner et al., 1991, 1993; Exley and Warner, 1999a). Those embryos with the Ped fast allele have a higher chance of their resulting pups surviving to term, and the pups have a higher birth weight and weaning weight compared with those pups arising from embryos with the Ped slow allele. Interestingly, both Ped fast and Ped slow embryos have an equal chance of surviving to midgestation; fetal loss occurs between midgestation and birth (Exley and Warner, 1999a). Thus, the Ped gene does not seem to influence whether implantation occurs, but rather the effect is on fetal survival later in pregnancy. Since embryos with the Ped fast allele have a higher number of cells both in their trophectoderm (TE) and inner cell mass (ICM) (McElhinny et al., 1998), this may lead to better vascularized implantation sites, better placentation, and enhanced fetal development even though implantation rates are similar for Ped fast and Ped slow embryos. There are many possibilities to explain

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

173

fetal loss of Qa-2-negative fetuses between midgestation and birth. These include a possible protective role of Qa-2 in warding off attack by maternal NK cells, CTLs, or macrophages, similar to the mechanisms illustrated previously in Fig. 3 (see color plates). It is also possible that the Ped gene influences growth and health throughout adult life; life span has been suggested to be affected by the Ped gene (Tarin, 1997), but this suggestion has not been tested experimentally. The Ped gene is a good example of how growth during the preimplantation period influences subsequent embryo survival and health later in life. There are other examples of this same phenomenon. For instance, knocking out the gene for alkaline phosphatase (EAP) results in slower development during the preimplantation period, a longer gestation time, and smaller litter size, similar to the effects described above for the Ped gene (Dehghani et al., 2000). Thus, certain genes can be deleted from the mouse genome (e.g., Q7, Q9, and EAP) with the result that reproductive capacity of the embryos is diminished, but not completely abolished. 2. A Human Homolog of the Mouse Ped Gene Since the mouse Ped gene has such an important influence on overall reproductive success, it would be most interesting to identify a similar gene in humans. The Ped gene phenotype, a range of developmental stages among embryos fertilized at the same time coupled to preferential survival of the faster developing embryos, exists in the human population, as well as in other animal species including mice, rats, hamsters, pigs, cows, and monkeys (Wilmut et al., 1986; Bazer et al., 1988; McKiernan and Bavister, 1994; Gonzales et al., 1995; Warner et al., 1998a–c; Cohen et al., 1999; Edwards and Beard, 1999). Thousands of slow-developing human embryos have been carefully checked for dozens of morphological criteria and chromosomal abnormalities, with the conclusion that a large proportion of slow-developing embryos are perfectly healthy and can give rise to healthy offspring, although there is a greater chance of obtaining a successful pregnancy when the faster developing embryos are used for embryo transfer (Buster et al., 1985; Cummins et al., 1986; Claman et al., 1987; Puissant et al., 1987; Clark, 1988; Bolton et al., 1989; Levy et al., 1991; Trounson and Osborn, 1993; Warner et al., 1998a; Trounson and Gardner, 2000). Figure 6 shows a picture of two healthy human embryos fertilized by IVF at the same time, but showing different rates of development 3 and 4 days later. Thus, the two major hallmarks of the mouse Ped gene phenotype, a range of developmental stages among preimplantation embryos fertilized at the same time and preferential survival of the faster developing embryos, is present in the human population. The challenge is to identify the genes that regulate rate of development and fetal survival in humans. Data suggest that human HLA-G is the functional homolog of mouse Qa-2, the Ped gene product (Allcock et al., 2000). This conclusion is based on the analysis of the complete DNA sequence of the human MHC, the HLA complex (Beck et al., 1999; Beck and Trowsdale, 2000), along with new findings about the expression

Textures 2.0

06/12/2001

02:49 PM

174

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

Figure 6 Fast- and slow-developing human embryos.

and function of HLA-G (reviewed in Le Bouteiller and Blaschitz, 1999). Although Qa-2 and HLA-G are not strict genetic orthologs, they are believed to be functional homologs as the result of convergent evolution (Allcock et al., 2000). Table IV shows a comparison of many of the features of Qa-2 and HLA-G (based on the following articles and references cited within: Cai et al., 1996; Stroynowski and Tabaczewski, 1996; Manilay and Sykes, 1998; O’Callaghan and Bell, 1998; Warner et al., 1998a–c; Braud et al., 1999; Cao et al., 1999; Fernandez et al., 1999; Hiby et al., 1999; Le Bouteiller and Blaschitz, 1999; Munz et al., 1999; Ke and Warner, 2000; McElhinny and Warner, 2000; Morales et al., 2000). Table IV shows that the vast majority of properties of Qa-2 and HLA-G are similar, with only one major difference. This difference is that Qa-2 is attached to the cell membrane by a glycosylphosphatidylinositol (GPI) linkage whereas HLA-G is simply inserted into the cell membrane by a short (six-amino acid) tail. We originally thought that this might have important functional significance (Cao

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

175

4. Genetic Regulation of Preimplantation Embryo Survival Table IV Comparison of HLA-G and Qa-2, the Ped Gene Producta Feature MHC class Ib molecule DNA sequence Membrane-bound and soluble forms Attached to membrane by a short tail GPI linkage of short tail to membrane Limited tissue expression Expression by preimplantation embryos Expression by placenta Nonapeptides bound Amino acid frequency Peptide sequences Same peptides in membrane and soluble forms Cell surface expression dependent on TAP Increased expression with IFN-γ Increased cell proliferation with cross-linking Deletion polymorphism compatible with embryo survival Interacts with T cell receptor (TCR) Interacts with CD8 (on T cells) Interacts with NK cell receptors Interacts with other accessory proteins Acts as a signal transduction molecule Effect on Ped gene phenotype Increases preimplantation growth rate Enhances fetal survival Increases birth weight Increases weaning weight

Qa-2

HLA-G

Yes Similar to HLA-G Yes Yes Yes Yes Yes Yes

Yes Similar to Qa-2 Yes Yes No Yes Yes Yes

Similar to HLA-G Unknown Unknown Yes Yes Yes Yes

Similar to Qa-2 Self-peptides Yes Yes Yes Unknown Yes

Yes Yes Unknown Probable Probable

Yes Yes Yes Unknown Unknown

Yes Yes Yes Yes

Yes Yes Unknown Unknown

a Based on Cai et al. (1996), Stroynowski and Tabaczewski (1996), Manilay and Sykes (1998), Warner et al. (1998a–c), O’Callaghan and Bell (1998), Braud et al. (1999), Cao et al. (1999), Fernandez et al. (1999), Hiby et al. (1999), Le Bouteiller and Blaschitz (1999), Munz et al. (1999), Ke and Warner (2000), McElhinny and Warner (2000), and Morales et al. (2000).

et al., 1999), but in further researching this finding we discovered that a short tail (six amino acids, as is found in HLA-G) confers many of the same properties to proteins as a GPI linkage: increased lateral mobility in the membrane, higher cell surface half-life, and a requirement for accessory proteins to transmit a signal across the membrane (Medof et al., 1996; Davis et al., 1997). We therefore now believe that the GPI linkage of Qa-2 is not likely to be a defining feature of its function. However, the GPI linkage of Qa-2 does provide an unusual experimental opportunity: GPI-linked proteins can be spontaneously incorporated into plasma membranes in a procedure called “protein painting,” to cause a transient change in the phenotype of the painted cell (McElhinny et al., 2000).

Textures 2.0

06/12/2001

02:49 PM

176

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

For HLA-G to be a functional homolog of Qa-2 in conferring the Ped phenotype, it must be expressed in human embryos. Four sets of human embryos have been analyzed for mRNA for HLA-G. Three of these studies analyzed almost 300 human embryos and found that 40–90% of the embryos were positive for HLA-G mRNA depending on the primers that were used (Jurisicova et al., 1996a,b, 1999; Cao et al., 1999). The fourth study did not find any HLA-G mRNA in the human embryos that they analyzed, but their sample size was only 11 embryos (Hiby et al., 1999). The reasons for these negative results are unknown, but include the sensitivity of the assay used, the particular HLA-G primers used, the developmental stage of the embryos tested, and the ethnic makeup of the donors of the embryos. One must conclude from these studies that a significant proportion of human preimplantation embryos express mRNA for HLA-G. However, as pointed out previously, mRNA levels are not necessarily indicative of protein levels. One of the above-cited studies did measure protein expression for HLA-G in human embryos (Jurisicova et al., 1996a), and this study did, indeed, find a correlation of rate of embryonic development with HLA-G protein expression. Thus, these results corroborate the idea that HLA-G is a functional homolog of Qa-2, the Ped gene product. It should be pointed out that studies of expression of HLA-G in human embryos are complicated by the outbred nature of the human population. There are presently 14 known alleles of HLA-G (Morales et al., 2000), and the allelic frequencies differ among different ethnic groups (e.g., Alizadeh et al., 1993; Karhukorpi et al., 1996; Ober et al., 1998; van der Ven et al., 1998a,b; Penzes et al., 1999; Yamashita et al., 1999). Therefore, further studies are needed to fully understand the significance of the expression of different alleles in reproductive success. Interestingly, we have found that the presence of particular alleles of HLA-G in women attending an IVF clinic makes pregnancy success after IVF more likely to occur (Warner et al., 2001). It has been suggested that HLA-G may help protect fetuses from destruction by the maternal immune system by inhibiting NK cells, T cells, and/or myelomonocytic cells, thus enhancing the probability of fetal survival (Pazmany et al., 1996; King et al., 1997; Pende et al., 1997; Rouas-Freiss et al., 1997a,b; Rolstad and Seaman, 1998; Allan et al., 1999; Le Gal et al., 1999; Munz et al., 1999). A complete understanding of the role of HLA-G in the regulation of preimplantation embryo survival remains to be elucidated.

C. Genes That Regulate Cell Cycle Processes Cell cycle signals have been observed in both mouse and human preimplantation oocytes and embryos. These signals occur in gametes during the period preceding fertilization and are induced in the oocyte by the fertilizing spermatozoon on gamete fusion. Possible mechanisms of abnormal cell cycle signaling can impair oocyte maturation and embryo development. These mechanisms may include

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

177

failure of first and second meiotic divisions leading to aneuploidy; incomplete failure of the second meiotic division, leading to de novo chromosomal numerical abnormalities; abnormal pronuclear development and function; and abnormalities of the blastomere cell cycle, possibly leading to embryo cleavage arrest or to mosaicisms and problems with blastomere allocation to embryonic cell lineages. Studies have led to significant improvements in the understanding of molecular mechanisms controlling cell division and growth. A key regulator of these processes has been shown to be maturation promoting factor (MPF). Molecular characterization of MPF has shown that active MPF is a protein dimer composed of a catalytic serine/threonine kinase subunit (p34cdc2 kinase) and a regulatory cyclin B subunit. Nuclear laminins and histone H1 are some of the substrates that are phosphorylated by p34cdc2 kinase; thus MPF has been proposed to be involved in several features of cell division, such as disassembly of the nucleus and chromosome condensation. Periodic activity is a characteristic of MPF since it is needed for each cell division. A protein kinase that has been implicated in upregulation of MPF activity both at the reinitiation of meiosis and during metaphase arrest, is the cellular component of the viral oncogene mos. c-Mos kinase has been proposed to enhance MPF activity via several mechanisms. In mouse oocytes, c-Mos kinase has been proposed to inhibit proteolytic degradation of cyclin B, which in turn leads to accumulation of cyclin-β 1 between meiosis I and II and thus maintains the high MPF activity seen during metaphase arrest. The mRNA expression patterns of the cell cycle genes, c-mos and cyclin-β 1, have been characterized in both mouse and human oocytes and embryos by both qualitative and semiquantitative RT-PCR. The protooncogene c-mos is expressed as a maternal message in an oocyte-specific manner (O’Keefe et al., 1991; Heikinheimo and Gibbons, 1998). The expression of c-mos is transient and little c-mos mRNA can be detected in the human embryo, suggesting meiosis-stage functions for c-mos in the human oocyte. As judged by the disappearance of c-Mos, the maternal pool seems to be degraded by the six- to eight-cell stage before ZGA. Lack of c-Mos might thus allow the two stages of meiosis to continue uninterrupted, resulting in parthenogenic activation. By using specific mRNA degradation by double-stranded RNA (dsRNA), which is termed RNA interference, the targeted reduction of c-mos mRNA in mouse oocytes resulted in parthenogenic activation (Svoboda et al., 2000). On the other hand, abundant expression of cyclin-β 1 seen in both mouse and human oocytes and in embryos from the six-cell stage onward indicates that active transcription and activation of the embryonic genome is necessary for mitotic cell division. The current model of eukaryotic cell cycle regulation suggests that there is an oscillating biochemical clock, which is regulated by surveillance systems, called cell cycle checkpoints. The spindle assembly checkpoint modulates the timing of anaphase initiation in response to the improper alignment of chromosomes at the metaphase plate. If defects are detected, a signal is transduced to halt further progression of the cell cycle until correct bipolar attachment to the spindle is achieved. MAD2 and BUB1 genes encode conserved kinetochore-associated

Textures 2.0

06/12/2001

02:49 PM

178

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

proteins believed to be components of the checkpoint regulatory pathway. A failure in this surveillance system could lead to genomic instability that may underlie the increased incidence of aneuploidy in the gametes of older women. To explore this possibility, the copy number of these transcripts has been determined in human oocytes at various stages of maturation, using a real-time rapid cycle fluorescence RT-PCR method (Steuerwald et al., 1999, 2000b, 2001). The results obtained following quantitative analysis suggest that these messages degrade as oocytes age. Potentially, this may impair checkpoint function in older oocytes and may be a contributing factor to age-related aneuploidy (Steuerwald et al., 2001). Work now confirms the presence of the MAD2 protein at the kinetochores of normal, seconddivision mouse oocytes at metaphase (A. Blaszczyk et al., unpublished, 2001). It has also been postulated that postzygotic errors in cell cycle checkpoint gene expression in human embryos may lead to genomic instabilities causing chromosomal mosaicisms (D. Wells et al., unpublished results, 2001).

VI. Genes That Regulate Preimplantation Death There is a current fascination with the topic of cell death, with more than 20,000 publications appearing on this topic in the past 5 years (Golstein, 1998). The reason is that cell death affects crucial normal and pathological biological processes such as development, aging, and cancer, in a wide range of organisms from the nematode Caenorhabditis elegans to humans. Cell death can occur by necrosis or apoptosis. Most of the fascination with cell death has centered on apoptosis because the molecular pathways leading to apoptosis have yielded to biochemical characterization. The pioneering work on genes that mediate apoptosis in C. elegans (Ellis and Horvitz, 1986) has led to the definition of three mammalian genes (or gene families) homologous to three genes in C. elegans that mediate apoptosis: ced-3, which encodes a protein product similar to mammalian caspases; ced-4, which encodes a product similar to mammalian Apaf-1; and ced-9, which encodes a product similar to the mammalian Bcl-2 family of proteins. The first suggestion that apoptosis occurs in embryos was made in 1974 (ElShershaby and Hinchcliffe, 1974). This study and subsequent studies have suggested that a few cells in normal blastocysts die by apoptosis in what appears to be part of a normal developmental program (El-Shershaby and Hinchliffe, 1974; Mohr and Trounson, 1982; Handyside and Hunter, 1986; Hardy et al., 1989; Pierce et al., 1989; Parchment, 1993; Hardy, 1997, 1999; Warner et al., 1998b; Exley et al., 1999a). Abnormal preimplantation embryos often have extensive cellular fragmentation suggesting that they are undergoing death by apoptosis (Jurisicova et al., 1996c, 1998a,b; Levy et al., 1997; Warner et al., 1998c; Yang et al., 1998). DNA fragmentation has been observed with the TUNEL [terminal deoxynucleotidyl transferase [TdT]-mediated dUTP nick-end labeling]

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

179

assay (Ben-Sasson et al., 1995) in fragmented blastomeres, confirming that many fragmented embryonic cells die by apoptosis (Jacobsen et al., 1996; Jurisicova et al., 1996c; Weil et al., 1996; Brison and Schultz, 1997, 1998; Levy et al., 1998; Warner et al., 1998c; Exley et al., 1999). In these studies the embryos were either induced to undergo fragmentation by withdrawal of growth factors or introduction of drugs, or were found in a fragmented state after development in vivo or in vitro. Studies of the genes that regulate apoptosis in preimplantation embryos are still in their infancy. A few studies have appeared showing by RT-PCR that members of the Bcl-2 and caspase families of genes are transcribed in preimplantation mouse and human embryos (Moley et al., 1998; Warner et al., 1998a–c; Jurisicova et al., 1998a; Exley et al., 1999). In addition, caspase 3 activity, a hallmark of apoptosis, has been detected in fragmented preimplantation embryos (Exley et al., 1999). Bcl-2 and Bax protein have been shown to be present in both normal and fragmented preimplantation mouse embryos (Moley et al., 1998; Exley et al., 1999), and there is some indication that the ratio of Bcl-2 to Bax may influence whether an embryo lives or dies during the preimplantation period of development (Moley et al., 1998; Exley et al., 1999). An intriguing set of studies has shown that hyperglycemia can induce apoptosis in preimplantation mouse embryos (Moley et al., 1998; Moley, 1999). Hyperglycemia in diabetic mice and humans during the preimplantation period not only leads to a decreased rate of preimplantation development and some preimplantation embryonic death, but can also lead to fetal loss during gestation and to congenital malformations. It is hypothesized that the mechanism of the effect of excess glucose is indirect. Two possibilities are that excess glucose induces uterine secretion of tumor necrosis factor α (TNF-α), a known inducer of apoptosis, and that excess glucose shuts down glucose transport into the embryo, which also induces apoptosis. Both of these mechanisms would result in the experimentally observed decrease in the number of cells in the ICM. And it is known that a critical number of cells in the ICM is required for normal development and pregnancy outcome (Tam, 1988; Brison and Schultz, 1996; Lane and Gardner, 1997; Van Soom et al., 1997; Chan et al., 2000). Thus, the effect of maternal hyperglycemia on preimplantation embryos is another example, along with those cited previously, that growth during the preimplantation period of development has a marked effect on later development and health.

VII. Conclusions Genes regulate mammalian preimplantation embryo survival. In this review we have considered the expression of genes of both nuclear and mitochondrial origin and their effect on preimplantation embryonic development, growth, and death. We have emphasized the mouse as a model system, and have included data on

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

180

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

human embryos wherever possible. One major theme is that what happens to an embryo during the preimplantation period of development, whether of genetic or environmental origin, can influence health later in life. Another theme that we have emphasized is that the rate of preimplantation development and the number of cells in the ICM both have a marked effect on subsequent embryo health and survival. In a larger overview, the evaluation of mammalian preimplantation embryonic health and the assessment of the chance that a particular embryo will implant in the uterus and survive to term are provided by two complementary technologies, morphological assessment and genetic analysis. Advances in preimplantation embryo imaging using state-of-the-art technologies such as two-photon laser scanning fluorescence microscopy, polarization microscopy, and quadrature tomographic microscopy (Stott et al., 2001) are underway in a number of laboratories, including our own. Embryo imaging is an exciting new field and the data garnered by these new imaging modalities may in due course significantly enhance and complement the genetic data discussed in this review. We are at the cusp of a revolution in biology with the acquisition of the complete DNA sequence of the human genome and the imminent availability of the sequence of the mouse genome. Thus, large amounts of data from imaging and genetic studies present a challenge for analysis by new methods being developed by researchers working in bioinformatics and data management. The start of the new millennium is an exciting time for biological research. One of the most fascinating fields in biology is the study of preimplantation embryonic development. Preimplantation embryos are being used for a variety of emerging reproductive technologies including IVF, intracytoplasmic sperm injection (ICSI), preimplantation genetic diagnosis, nuclear transfer, cytoplasmic transfer, and the creation of embryonic stem (ES) cells. With the perfection of cloning technologies in animal models, it will be possible in the near future to clone humans. In addition to cloning, ES cells derived from human preimplantation embryos may soon be used for transplantation after their differentiation into particular tissues and organs is perfected. Extensive discussions of scientific benefits and risks of these new technologies, as well as the ethical and moral aspects of the new techniques, are currently underway. These are exciting times for preimplantation embryo research. The future is here!

Acknowledgments We are grateful for financial support from the NIH (HD31505, HD39215, HD40309), the NSF Engineering Research Center for Subsurface Sensing and Imaging Systems (CenSSIS) (EEC-9986821), and the Institute for Reproductive Medicine and Science of Saint Barnabas Medical Center. We also express appreciation to Judy Newmark and Mina Alikani for providing the images of mouse and human embryos, and to Judy Newmark and Martina Comiskey for critical reading of this manuscript.

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

181

References Abdel-Rahman, B., Fiddler, M., Rappolee, D., and Pergament, E. (1995). Expression of transcription regulating genes in human preimplantation embryos. Hum. Reprod. 10, 2787–2792. Alizadeh, M., Legras, C., Semana, G., LeBouteiller, P., Genetet, B., and Fauchet, R. (1993). Evidence for a polymorphism of HLA-G gene. Hum. Immunol. 38, 206–212. Allan, D. S. J., Colonna, M., Lanier, L. L., Churkakova, T. D., Abrams, J. S., Ellis, S. A., McMichael, A. J., and Braud, V. M. (1999). Tetrameric complexes of human histocompatibility complex leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells. J. Exp. Med. 189, 1149–1155. Allcock, R. J. N., Martin, A. M., and Price, P. (2000). The mouse as a model for the effects of MHC genes on human disease. Immunol. Today 21, 328–332. Anderson, L., and Seilhamer, J. (1997). A comparison of selected mRNA and protein abundances in human liver. Electrophoresis 18, 533–537. Athanasas-Platsis, S., Corcoran, C. M., Kaye, P. L., Cavanagh, A. C., and Morton, H. (2000). Early pregnancy factor is required at two important stages of embryonic development in the mouse. Am. J. Reprod. Immunol. 43, 223–233. Barker, D. J. P. (1995). Fetal origins of coronary heart disease. Br. Med. J. 311, 171–174. Barritt, J. A., Brenner, C. A., Cohen, J., and Matt, D. W. (1999). Mitochondrial DNA rearrangements in human oocytes and embryos. Mol. Hum. Reprod. 5, 927–933. Barritt, J. A., Brenner, C. A., Willadsen, S., and Cohen, J. (2000a). Spontaneous and artificial changes in human ooplasmic mitochondria. Hum. Reprod. 15, 207–217. Barritt, J. A., Cohen, C., and Brenner, C. A. (2000b). Mitochondrial DNA point mutation in human oocytes is associated with maternal age. Reprod. BioMed. 1, 96–100. Barritt, J. A., Brenner, C. A., Matter, H. E., and Cohen, J. (2001). Mitochondria in human offspring derived from ooplasmic transplantation. Hum. Reprod. 16, 513–516. Bavilacqua, A., Fiorenza, M. T., and Mangia, F. (2000). A developmentally regulated GAGA box-binding factor and Sp1 are required for transcription of the hsp70.1 gene at the onset of mouse zygotic genome activation. Development 127, 1541–1551. Bazer, F. W., Thatcher, W. W., Martinat-Botte, F., and Terqui, M. (1988). Conceptus development in large white and prolific Chinese Meishan pigs. J. Reprod. Fertil. 84, 37–42. Bazer, F. W., Geisert, R. D., and Zavy, M. T. (1993). Fertilization, cleavage and implantation. In “Reproduction in Farm Animals” (E. S. E. Hafez, Ed.), 6th ed., pp. 188–212. Lea & Febiger Philadelphia, Pennsylvania. Beck, S., and Trowsdale, J. (2000). The human major histocompatibility complex: Lessons from the DNA sequence. Annu. Rev. Genomics Hum. Genet. 1, 117–137. Beck, S., Geraghty, D., Inoko, H., Rowen, L., and MHC Sequencing Consortium. (1999). Complete sequence and gene map of a human major histocompatibility complex. Nature (London) 401, 921–923. Ben-Sasson, S. A., Sherman, Y., and Gavrielli, Y. (1995). Identification of dying cells—in situ staining. Methods Cell Biol. 46, 29–39. Ben-Shushan, E., Thompson, J. R., Gudas, L. J., and Bergman, Y. (1998). Rex-1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct-3/4 and Oct-6 binding to an octamer site and a novel protein, Rox-1, binding to an adjacent site. Mol. Cell. Biol. 18, 1866–1878. Biggers, J. D. (1998). Reflections on the culture of the preimplantation embryo. Int. J. Dev. Biol. 42, 879–884. Bolton, V. N., Hawes, S. M., Taylor, C. T., and Parsons, J. H. (1989). Development of spare human preimplantation embryos in vitro: An analysis of the correlations among gross morphology, cleavage rates, and development to the blastocyst. J. In Vitro Fertil. Embryo Transfer 6, 30–35.

Textures 2.0

06/12/2001

02:49 PM

182

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

Bossert, N. L., Hitselberger, M. H., and Iannaccone, P. M. (1990). Protein alterations associated with N-methyl-N-nitrosourea exposure of preimplantation mouse embryos transferred to surrogate mothers. Teratology 42, 147–156. Braud, V., Allan, D. S. J., and McMichael, A. J. (1999). Functions of nonclassical MHC and non-MHC-encoded class I molecules. Curr. Opin. Immunol. 11, 100–108. Braude, P. R., Bolton, V., and Moore, S. (1988). Human gene expression first occurs between the four and eight-cell stages of preimplantation development. Nature (London) 332, 459–461. Brenner, C., and Cohen, J. (2000). The genetic revolution in artificial reproduction: A view of the future. Hum. Reprod. 15, 101–106. Brenner, C. A., Adler, R. R., Rappolee, D. A., Pedersen, R. A., and Werb, Z. (1989). Metalloproteinases and their inhibitor, TIMP, are expressed during early mammalian development. Genes Dev. 6, 848–859. Brenner, C. A., Wolny, Y. M., Barritt, J. A., Matt, D. W., Munne, S., and Cohen, J. (1998). Mitochondrial DNA deletion in human oocytes and embryos. Mol. Hum. Reprod. 4, 887–892. Brenner, C. A., Wolny, Y. M., Adler, R. R., and Cohen, J. (1999). Alternative splicing of the telomerase catalytic subunit in human oocytes and embryos. Mol. Hum. Reprod. 5, 845–850. Brenner, C. A., Barritt, J. A., Willadsen, S., and Cohen, J. (2000). Mitochondrial DNA heteroplasmy after human ooplasmic transplantation. Fertil. Steril. 74, 573–578. Brinster, R. I. (1967). Protein content of the mouse embryo during the first five days of development. J. Reprod. Fertil. 13, 413–420. Brison, D. R., and Schultz, R. M. (1996). RT-PCR-based method to localize the spatial expression of genes in the mouse blastocyst. Mol. Reprod. Dev. 44, 171–178. Brison, D. R., and Schultz, R. M. (1997). Apoptosis during mouse blastocyst formation: Evidence for a role for survival factors including transforming growth factor α. Biol. Reprod. 56, 1088–1096. Brison, D. R., and Schultz, R. M. (1998). Increased incidence of apoptosis in transforming growth factor α-deficient mouse blastocysts. Biol. Reprod. 59, 136–144. Brownell, M. S., and Warner, C. M. (1988). Ped gene expression by embryos cultured in vitro. Biol. Reprod. 39, 806–811. Buster, J. E., Burillo, M., Rodi, I. A., Cohen, S. W., Hamilton, M., Simon, J. A., Thorneycroft, I. H., and Marshall, S. R. (1985). Biologic and morphologic development of donated human ova recovered by non-surgical uterine lavage. Am. J. Obstet. Gynecol. 153, 211–217. Cai, W., Cao, W., Wu, L., Exley, G. E., Waneck, G. L., Karger, B. L., and Warner, C. M. (1996). Sequence and transcription of Qa-2-encoding genes in mouse lymphocytes and blastocysts. Immunogenetics 45, 97–107. Cao, W., Brenner, C. A., Alikani, M., Cohen, J., and Warner, C. M. (1999). Search for a human homologue of the mouse Ped gene. Mol. Hum. Reprod. 5, 541–547. Cebral, E., Lasserre, A., Rettori, V., and de Gimeno, M. A. (1999). Deleterious effects of chronic moderate alcohol intake by female mice on preimplantation embryo growth in vitro. Alcohol Alcohol. 34, 551–558. Cebral, E., Lasserre, A., Rettori, V., and de Gimeno, M. A. (2000). Alterations in preimplantation in vivo development after preconceptional chronic moderate alcohol consumption in female mice. Alcohol Alcohol. 35, 336–343. Chan, A. W. S., Dominko, T., Luetjens, C. M., Neuber, E., Martinovich, C., Hewitson, L., Simerly, C. R., and Schatten, G. P. (2000). Clonal propagation of primate offspring by embryo splitting. Science 287, 317–319. Chen, X., Prosser, R., Simonetti, S., Sadlock, J., Jagiello, G., and Schon, E. A. (1995). Rearranged mitochondrial genomes are present in human oocytes. Am. J. Hum. Genet. 57, 239–247. Cheng, C. C., Sege, K., Alton, A. K., Bennett, D., and Artzt, K. (1983). Characterization of an antigen present on testicular cells and preimplantation embryos whose expression is modified by the t12 haplotype. J. Immunogenet. 10, 465–485.

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

183

Claman, P., Armant, D. R., Seibel, M. M., Wang, T. A., Oskowitz, S. P., and Taymor, M. L. (1987). The impact of embryo quality and quantity on implantation and the establishment of viable pregnancies. J. In Vitro Fertil. Embryo Transfer 4, 218–222. Clark, D. A. (1988). Host immunoregulatory mechanisms and the success of the conceptus in vivo and in vitro. In “Early Pregnancy Loss: Mechanisms and Treatment” (R. W. Beard and R. Sharp, Eds.), pp. 215–232. Peacock Press, London. Clerc, P., and Avner, P. (2000). Reprogramming X inactivation. Science 290, 1518–1519. Cohen, J., Alikani, M., Malter, H. E., Adler, A., Talansky, B. E., and Rosenwaks, Z. (1991). Partial zona dissection or subzonal sperm insertion: Microsurgical fertilization alternatives based on the evaluation of sperm and embryo morphology. Fertil. Steril. 56, 696–706. Cohen, J., Scott, R., Alikani, M., Schimmel, T., Munne, S., Levron, J., Wu, L., Brenner, C., Warner, C., and Willadsen, S. (1998). Ooplasmic transfer in mature human oocytes. Mol. Hum. Reprod. 4, 269–280. Cohen, J., Brenner, C., Warner, C., Steuerwald, N., Sadowy, S., Barritt, J., Sandalinas, M., and Munne, S. (1999). Genetics of the fertilizing egg. In “Towards Reproductive Certainty: Fertility and Genetics beyond 1999” (R. Jansen and D. Mortimer Eds.), pp. 231–246. Parthenon Publishing Group, New York. Cortopassi, G. A., and Arnheim, N. (1990). Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic. Acid Res. 18, 6927–6933. Cummins, J. M., Breen, T. M., Harrison, K. L., Shaw, J. M., Wilson, L. M., and Hennessey, J. F. (1986). A formula for scoring human embryo growth rates in in vitro fertilization: Its value in predicting pregnancy and a comparison with visual estimates of embryo quality. J. In Vitro Fertil. Embryo Transfer 3, 284–295. Davies, J., and Hesseldahl, H. (1971). Comparative embryology of mammalian blastocysts. In “The Biology of the Blastocyst” (R. J. Blandau, Ed.), pp. 27–48. The University of Chicago Press, Chicago. Davis, D. M., Reyburn, H. T., Pazmany, L., Chiu, I., Mandelboim, O., and Strominger, J. L. (1997). Impaired spontaneous endocytosis of HLA-G. Eur. J. Immunol. 27, 2714–2719. Dehghani, H., Narisawa, S., Millan, J. L., and Hahnel, A. C. (2000). Effects of disruption of the embryonic alkaline phosphatase gene on preimplantation development of the mouse. Dev. Dyn. 217, 440–448. Diaz-Cueto, L., Stein, P., Jacobs, A., Schultz, R. M., and Gerton, G. L. (2000). Modulation of mouse preimplantation embryo development by acrogranin (epithelin/granulin precursor). Dev. Biol. 217, 406–418. Doherty, A. S., Mann, M. R., Tremblay, K. D., Bartolomei, M. S., and Schultz, R. M. (2000). Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol. Reprod. 62, 1526–1535. Dumoulin, J. C. M., Menheere, P. P. C. A., Evers, J. L. H., Kleukers, A. P. G., Pieters, M. H. E. C., Bras, M., and Geraedts, J. P. M. (1991). The effects of endotoxins on gametes and preimplantation embryos cultured in vitro. Hum. Reprod. 6, 730–734. Edwards, R. G., and Beard, H. K. (1999). Is the success of human IVF a matter of developmental biology? In “Towards Reproductive Certainty: Fertility and Genetics beyond 1999” (R. Jansen and D. Mortimer, Eds.), pp. 414–420. Parthenon Publishing Group, New York. Eggan, K., Akutsu, H., Hochedlinger, K., Rideout, W., III, Yanagimachi, R., and Jaenisch, R. (2000). Chromosome inactivation in cloned mouse embryos. Science 290, 1578–1581. Ellis, H. M., and Horvitz, H. R. (1986). Genetic control of programmed cell death in the nematode C. elegans. Cell 44, 817–829. El-Shershaby, A. M., and Hinchcliffe, J. R. (1974). Cell redundancy in the zona-intact preimplantation mouse blastocyst: A light and electron microscope study of dead cells and their fate. J. Embryol. Exp. Morphol. 31, 643–654.

Textures 2.0

06/12/2001

02:49 PM

184

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

Emerson, M., Travis, A. R., Bathgate, R., Stojanov, T., Cook, D. I., Harding, E., Lu, D. P., and O’Neill, C. (2000). Characterization and functional significance of calcium transients in the 2-cell mouse embryo induced by an autocrine factor. J. Biol. Chem. 275, 21905–21913. Ewoldsen, M. A., Ostlie, N. S., and Warner, C. M. (1987). Killing of mouse blastocyst stage embryos by cytotoxic T lymphocytes directed to major histocompatibility complex antigens. J. Immunol. 138, 2764–2770. Exley, G. E., and Warner, C. M. (1999a). Selection in favor of the Ped fast haplotype occurs between mid-gestation and birth. Immunogenetics 49, 653–659. Exley, G. E., and Warner, C. M. (1999b). Zygotic genomic activation. In “Encyclopedia of Reproduction” (E. Knobil and J. D. Neill, Eds.), pp. 1041–1046. Academic Press, San Diego, California. Exley, G. E., Tang, C., McElhinny, A. S., and Warner, C. M. (1999). Expression of caspase and BCL-2 apoptotic family members in mouse preimplantation embryos. Biol. Reprod. 61, 231–239. Fernandez, N., Cooper, J., Sprinks, M., AbdElrahman, M., Fiszer, D., Kurpisz, M., and Dealtry, G. (1999). A critical review of the role of the major histocompatibility complex in fertilization, preimplantation development and feto-maternal interactions. Hum. Reprod. Update 5, 234–248. Gardner, D. K. (1998). Changes in requirements and utilization of nutrients during mammalian preimplantation embryo development and their significance in embryo culture. Theriogenology 49, 83–102. Gardner, D. K., and Schoolcraft, W. B. (1999). Culture and transfer of human blastocysts. Curr. Opin. Obstet. Gynecol. 3, 307–311. Gardner, R. L. (1997). The early blastocyst is bilaterally symmetrical and its axis of symmetry is aligned with the animal–vegetal axis of the zygote in the mouse. Development 124, 289–301. Gill, T. J., III (1999). Mechanisms of action of major-histocompatibility-complex-linked genes affecting reproduction. Am. J. Reprod. Immunol. 41, 23–33. Goldbard, S. B., Verbanac, K. M., and Warner, C. M. (1982a). Genetic analysis of H-2 linked gene(s) affecting early mouse embryo development. J. Immunogenet. 9, 77–82. Goldbard, S. B., Verbanac, K. M., and Warner, C. M. (1982b). Role of the H-2 complex in preimplantation mouse embryo development. Biol. Reprod. 26, 591–596. Golstein, P. (1998). Cell death in us and others. Science 281, 1283. Gonzales, D. S., Pinheiro, J. C., and Bavister, B. D. (1995). Prediction of the developmental potential of hamster embryos in vitro by precise timing of the third cell cycle. J. Reprod. Fertil. 105, 1–8. Goval, J. J., and Alexandre, H. (2000). Effect of genistein on the temporal coordination of cleavage and compaction in mouse preimplantation embryos. Eur. J. Morphol. 38, 88–96. Gurdon, J. B., and Colman, A. (1999). The future of cloning. Nature (London) 402, 743–746. Gygi, S. P., Rochon, Y., Franza, B. R., and Aebersold, R. (1999). Correlation between protein and mRNA abundance in yeast. Mol. Cell. Biol. 19, 1720–1730. Hall, J., Gilligan, A., Schimmel, T., Cecchi, M., and Cohen, J. (1998). The origin, effects and control of air pollution in laboratories used for human embryo culture. Hum. Reprod. 13, 146–155. Handyside, A. H., and Hunter, S. (1986). Cell division and death in the mouse blastocyst before implantation. Roux’s Arch. Dev. Biol. 195, 519–526. Hansis, C., Grifo, J. A., and Krey, L. C. (2000). Oct-4 expression in inner cell mass and trophectoderm of human blastocysts. Mol. Hum. Reprod. 6, 999–1004. Hardy, K. (1993). Development of human blastocysts in vitro. In “Preimplantation Embryo Development” (B. D. Bavister, Ed.), pp. 184–199. Springer-Verlag, New York. Hardy, K. (1997). Cell death in the mammalian blastocyst. Mol. Hum. Reprod. 3, 919–925. Hardy, K. (1999). Apoptosis in the human embryo. Rev. Reprod. 4, 125–134. Hardy, K., Handyside, A. H., and Winston, R. M. (1989). The human blastocyst: Cell number, death and allocation during late preimplantation development in vitro. Development 107, 597–604.

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

185

Hardy, K., Warner, A., Winston, R. M., and Becker, D. L. (1996). Expression of intercellular junctions during preimplantation development of the human embryo. Mol. Hum. Reprod. 2, 621–632. Heikinheimo, O., and Gibbons, W. E. (1998). The molecular mechanisms of oocyte maturation and early embryonic development are unveiling new insights into reproductive medicine. Mol. Hum. Reprod. 4, 745–756. Hendrey, J., Lin, D., and Dziadek, M. (1995). Developmental analysis of the Hbath-J mouse mutation: Effects on mouse peri-implantation development and identification of two candidate genes. Dev. Biol. 172, 253–263. Hiby, S. E., King, A., Sharkey, A., and Loke, Y. W. (1999). Molecular studies of trophoblast HLA-G: Polymorphism, isoforms, imprinting and expression in preimplantation embryo. Tissue Antigens 53, 1–13. Hogan, B., Beddington, R., Constantini, F., and Lacy, E. (1994). “Manipulating the Mouse Embryo.” Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York. Inoue, K., Nakada, K., Ogura, A., Isobe, K., Goto, Y., Nonaka, I., and Hayashi, J. I. (2000). Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nat. Genet. 26, 176–181. Jacobsen, M. D., Weil, M., and Raff, M. C. (1996). Role of Ced-3/ICE-Family proteases in staurosporine-induced programmed cell death. J. Cell Biol. 133, 1041–1051. Jumaa, H., Wei, G., and Nielsen, P. J. (1999). Blastocyst formation is blocked in mouse embryos lacking the splicing factor SRp20. Curr. Biol. 9, 899–902. Jurisicova, A., Casper, R. F., MacLusky, N. J., and Librach, C. L. (1996a). Embryonic human leukocyte antigen-G expression: Possible implications for human preimplantation development. Fertil. Steril. 65, 997–1002. Jurisicova, A., Casper, R. F., MacLusky, N. J., Mills, G. B., and Librach, C. L. (1996b). HLA-G expression during preimplantation human embryo development. Proc. Natl. Acad. Sci. U.S.A. 93, 161–165. Jurisicova, A., Varmuza, S., and Casper, R. F. (1996c). Programmed cell death and human embryo fragmentation. Mol. Hum. Reprod. 2, 93–98. Jurisicova, A., Latham, K. E., Casper, R. F., and Varmuza, S. L. (1998a). Expression and regulation of genes associated with cell death during murine preimplantation embryo development. Mol. Reprod. Dev. 51, 243–253. Jurisicova, A., Rogers, I., Fasciani, A., Casper, R. F., and Varmuza, S. (1998b). Effect of maternal age and conditions of fertilization on programmed cell death during murine preimplantation embryo development. Mol. Hum. Reprod. 4, 139–145. Jurisicova, A., Antenos, M., Kapasi, K., Meriano, J., and Casper, R. F. (1999). Variability in the expression of trophectodermal markers β-human chorionic gonadotrophin, human leukocyte antigen-G and pregnancy specific β-1 glycoprotein by the human blastocyst. Hum. Reprod. 14, 1852–1858. Karhukorpi, J., Ikaheimo, I., Silvennoinen-Kassinen, S., and Tiilikainen, A. (1996). HLA-G polymorphism and allelic association with HLA-A in a Finnish population. Eur. J. Immunogenet. 23, 153–155. Kaye, P. L. (1997). Preimplantation growth factor physiology. Rev. Reprod. 2, 121–127. Ke, X., and Warner, C. M. (2000). Regulation of Ped gene expression by TAP protein. J. Reprod. Immunol. 46, 1–15. Keefe, D. L., Niven-Fairchild, T., Powell, S., and Buradagunta, S. (1995). Mitochondrial deoxyribonucleic acid deletions in oocytes and reproductive aging in women. Fertil. Steril. 64, 577–583. Kemler, R., Babinet, C., Eisen, H., and Jacob, F. (1977). Surface antigen in early differentiation. Proc. Natl. Acad. Sci. U.S.A. 74, 4449–4452. Kidder, G. M., and McLachlin, J. R. (1985). Timing of transcription and protein synthesis underlying morphogenesis in preimplantation mouse embryos. Dev. Biol. 112, 265–275.

Textures 2.0

06/12/2001

02:49 PM

186

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

Kimmel, C. A., Generoso, W. M., Thomas, R. D., and Bakshi, K. S. (1993). A new frontier in understanding the mechanisms of developmental abnormalities. Toxicol. Appl. Pharmacol. 119, 159–165. King, A., Loke, Y. W., and Chaouat, G. (1997). NK cells and reproduction. Immunol. Today 18, 64–66. Ko, M. S., Kitchen, J. R., Wang, X., Threat, T. A., Wang, X., Hasegawa, A., Sun, T., Grahovac, M. J., Kargul, G. J., Lim, M. K., Cui, Y., Sano, Y., Tanaka, T., Liang, Y., Mason, S., Paonessa, P. D., Sauls, A. D., DePalma, G. E., Sharara, P., Rowe, L. B., Eppig, J., Morrell, C., and Doi, H. (2000). Large-scale cDNA analysis reveals phased gene expression patterns during preimplantation mouse development. Development 127, 1737–1749. Kowalik, A., Liu, H. C., He, Z. Y., Mele, C., Barmat, L., and Rosenwaks, Z. (1999). Expression of the insulin-like growth factor-1 gene and its receptor in preimplantation mouse embryos: Is it a marker of embryo viability?. Mol. Hum. Reprod. 5, 861–865. Kozik, A., Bradbury, E. M., and Zalensky, A. (1998). Increased telomere size in sperm cells of mammals with long terminal (TTAGGG)n arrays. Mol. Reprod. Dev. 1, 98–104. Kreidberg, J. A., Natoli, T. A., McGinnis, L., Donovan, M., Biggers, J. D., and Amstutz, A. (1999). Coordinate action of Wt1 and a modifier gene supports embryonic survival in the oviduct. Mol. Reprod. Dev. 52, 366–375. Krussel, J. S., Huang, H. Y., Hirchenhain, J., Bielfeld, P., Cupisti, S., Jeremias, L., and Polan, M. L. (2000). Is there a place for biochemical embryonic preimplantational screening? J. Reprod. Fertil. Suppl. 55, 147–159. Kwong, W. Y., Wild, A. E., Roberts, P., Willis, A. C., and Fleming, T. P. (2000). Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development 127, 4195–4202. Lane, M., and Gardner, D. K. (1992). Effect of incubation volume and embryo density on the development and viability of mouse embryos in vitro. Hum. Reprod. 7, 558–562. Lane, M., and Gardner, D. K. (1997). Differential regulation of mouse embryo development and viability by amino acids. J. Reprod. Fertil. 109, 153–164. Lane, M., and Gardner, D. K. (2000). Lactate regulates pyruvate uptake and metabolism in the preimplantation mouse embryo. Biol. Reprod. 62, 16–22. Lanza, R. P., Cibelli, J. B., Blackwell, C., Cristofalo, V. J., Francis, M. K., Baerlocher, G. M., Mak, J., Schertzer, M., Chavez, E. A., Sawyer, N., Lansdorp, P. M., and West, M. D. (2000). Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science 288, 665–669. Laub, D. N., Elmagbari, N. O., Elmagbari, N. M., Hausburg, M. A., and Gardiner, C. S. (2000). Effects of acetaminophen on preimplantation embryo glutathione concentration and development in vivo and in vitro. Toxicol. Sci. 56, 150–155. Le Bouteiller, P., and Blaschitz, A. (1999). The functionality of HLA-G is emerging. Immunol. Rev. 167, 233–244. Le Gal, F. A., Riteau, B., Sedlik, C., Khalil-Daher, I., Menier, C., Dausset, J., Guillet, J. G., Carosella, E. D., and Rouas-Freiss, N. (1999). HLA-G mediated inhibition of antigen-specific cytotoxic T lymphocytes. Int. Immunol. 11, 1351–1356. Levy, J. B., Johnson, M. H., Goodall, H., and Maro, B. (1986). The timing of compaction: Control of a major developmental transition in mouse early embryogenesis. J. Embryol. Exp. Morphol. 95, 213–237. Levy, R., Benchaib, M., Cordonier, H., Souchier, C., Guerin, J. F., and Czyba, J. C. (1997). Applications of laser scanning confocal microscopy to the observation of human oocytes and embryos. Ital. J. Anat. Embryol. 102, 141–153. Levy, R., Benchaib, M., Cordonier, H., Souchier, C., and Guerin, J. F. (1998). Annexin V labelling and terminal transferase-mediated DNA end labelling (TUNEL) assay in human arrested embryos. Mol. Hum. Reprod. 4, 775–783.

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

187

Levy, T., Goldman, J. A., Dicker, D., Ashkenazi, J., and Feldberg, D. (1991). Very early pregnancy wastage in in vitro fertilization and embryo transfer (IVF-ET). J. In Vitro Fertil. Embryo Transfer 8, 250–253. Liu, H., Wang, C. W., Grifo, J. A., Krey, L. C., and Zhang, J. (1999). Reconstruction of mouse oocytes by germinal vesicle transfer: Maturity of host oocyte cytoplasm determines meiosis. Hum. Reprod. 14, 2357–2361. Loutradis, D., Drakakis, P., Kallanidis, K., Sofikitis, N., Kallipolitis, G., Milingos, S., Makris, N., and Michalas, S. (2000). Biological factors in culture media affecting in vitro fertilization, preimplantation embryo development, and implantation. Ann. N.Y. Acad. Sci. 900, 325–335. MacPhee, D. J., Jones, D. H., Barr, K. J., Betts, D. H., Watson, A. J., and Kidder, G. M. (2000). Differential involvement of Na(+), K(+)-ATPase isozymes in preimplantation development of the mouse. Dev. Biol. 222, 486–498. Magnuson, T., Sharan, S. K., and Holdener-Kenny, B. (1993). Mutations affecting early development in the mouse. In “Preimplantation Embryo Development” (B. D. Bavister, Ed.), pp. 131–143. Springer-Verlag, New York. Manilay, J. O., and Sykes, M. (1998). Natural killer cells and their role in graft rejection. Curr. Opin. Immunol. 10, 532–538. McElhinny, A. S., and Warner, C. M. (1997). Detection of major histocompatibility complex class I antigens on the surface of a single murine blastocyst by Immuno-PCR. BioTechniques 23, 660–662. McElhinny, A. S., and Warner, C. M. (2000). Crosslinking of Qa-2 protein, the Ped gene product, increases the cleavage rate of C57BL/6 preimplantation mouse embryos. Mol. Hum. Reprod. 6, 517–522. McElhinny, A. S., Kadow, N., and Warner, C. M. (1998). The expression pattern of the Qa-2 antigen in mouse preimplantation embryos and its correlation with the Ped gene phenotype. Mol. Hum. Reprod. 4, 966–971. McElhinny, A. S., Exley, G. E., and Warner, C. M. (2000). Painting Qa-2 onto Ped slow preimplantation embryos increases the rate of cleavage. Am. J. Reprod. Immunol. 44, 52–58. McGrath, J., and Solter, D. (1984). Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37, 179–183. McKiernan, S. H., and Bavister, B. D. (1994). Timing of development is a critical parameter for predicting successful embryogenesis. Hum. Reprod. 9, 2123–2129. McKiernan, S. H., and Bavister, B. D. (2000). Culture of one-cell hamster embryos with water soluble vitamins: Pantothenate stimulates blastocyst production. Hum. Reprod. 15, 157–164. McLaren, A., and Bowman, P. (1973). Genetic effects on the timing of early development in the mouse. J. Embryol. Exp. Morphol. 30, 491–498. Medof, M. E., Nagarajan, S., and Tykocinski, M. L. (1996). Cell-surface engineering with GPI-anchored proteins. FASEB J. 10, 574–586. Menezo, Y., and Renard, J.-P. (1993). The life of the egg before implantation. In “Reproduction in Mammals and Man” (C. Thibault, M. C. Levasseur, and R. H. F. Hunter. Eds.), pp. 349–367. Ellipses, Paris. Mohr, L. R., and Trounson, A. O. (1982). Comparative ultrastructure of hatched human, mouse, and bovine blastocysts. J. Reprod. Fertil. 66, 499–504. Moley, K. H. (1999). Diabetes and preimplantation events of embryogenesis. Semin. Reprod. Endocrinol. 17, 137–151. Moley, K. H., Chi, M. M.-Y., Knudson, C. M., Korsmeyer, S. J., and Mueckler, M. M. (1998). Hyperglycemia induces apoptosis in preimplantation embryos through cell death effector pathways. Nat. Med. 4, 1421–1424. Morales, P., Martinez-Laso, J., Castro, M. J., Gomez-Casado, E., Alvarez, M., Rojo, R., Longas, J., Lowy, E., Rubio, I., and Arnaiz-Villena, A. (2000). An evolutionary overview of the MHC-G polymorphism: Clues to the unknown function(s). In “Major Histocompatibility Complex Evolution, Structure, and Function” (M. Kasahara, Ed.), pp. 463–479. Springer-Verlag, Tokyo.

Textures 2.0

06/12/2001

02:49 PM

188

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

Munz, C., Stevanovic, S., and Rammensee, H. G. (1999). Peptide presentation and NK inhibition by HLA-G. J. Reprod. Immunol. 43, 139–155. Nagao, T., Saitoh, Y., and Yoshimura, S. (2000). Possible mechanism of congenital malformations induced by exposure of mouse preimplantation embryos to mitomycin C. Teratology 61, 248–261. Nakamura, T. M., Morin, G. B., Chapman, K. B., Weinrich, S. L., Andrews, W. H., Lingner, J., Harley, C. B., and Cech, T. R. (1997). Telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955–959. Nieset, J. E., Redfield, A. R., Jin, F., Knudsen, K. A., Johnson, K. R., and Wheelock, M. J. (1997). Characterization of the interaction of α-catenin and α-actinin and β-catenin/plakoglobin. J. Cell Sci. 110, 1013–1022. Nikas, G., Ao, A., Winston, R. M., and Handyside, A. H. (1996). Compaction and surface polarity in the human embryo in vitro. Biol. Reprod. 55, 32–37. Ober, C., Aldrich, C., Rosinsky, B., Robertson, A., Walker, M. A., Willadsen, S., Verp, M. S., Geraghty, D. E., and Hunt, J. S. (1998). HLA-G1 protein expression is not essential for fetal survival. Placenta 19, 127–132. O’Callaghan, C. A., and Bell, J. I. (1998). Structure and function of the human MHC class Ib molecules HLA-E, HLA-F and HLA-G. Immunol. Rev. 163, 129–138. O’Keefe, S. J., Kiessling, A. A., and Cooper, G. M. (1991). The c-mos gene product is required for cyclin B accumulation during meiosis of mouse eggs. Proc. Natl. Acad. Sci. U.S.A. 88, 7869–7872. Olds, P. J., Stern, S., and Biggers, J. D. (1973). Chemical estimates of the RNA and DNA contents of the early mouse embryo. J. Exp. Zool. 186, 39–46. O’Neill, C. (1998). Autocrine mediators are required to act on the embryo by the 2-cell stage to promote normal development and survival of mouse preimplantation embryos in vitro. Biol. Reprod. 58, 1303–1309. Parchment, R. E. (1993). The implications of a unified theory of programmed cell death, polyamines, oxyradicals and histogenesis in the embryo. Int. J. Dev. Biol. 37, 75–83. Pauken, C. M., and Capco, D. G. (2000). The expression and stage-specific localization of protein kinase C isotypes during mouse preimplantation development. Dev. Biol. 223, 411–421. Pazmany, L., Mandelboim, O., Vales-Gomes, M., Davis, D. M., Reyburn, H. T., and Strominger, J. L. (1996). Protection from natural killer cell-mediated lysis by HLA-G expression on target cells. Science 274, 792–795. Pende, D., Sivori, S., Accame, L., Pareti, L., Falco, M., Geraghty, D., Le Bouteiller, P., Moretta, L., and Moretta, A. (1997). HLA-G recognition by human natural killer cells. Involvement of CD94 both as inhibitory and as activating receptor complex. Eur. J. Immunol. 27, 1875–1880. Pennisi, E., and Vogel, G. (2000). Clones: A hard act to follow. Science 288, 1722–1727. Penzes, M., Rajczy, K., Gyodi, E., Reti, M., Feher, E., and Petranyi, G. (1999). HLA-G polymorphism in the normal population and in recurrent spontaneous abortion in Hungary. Transplant. Proc. 31, 1832–1833. Pergament, E., and Fiddler, M. (1998). The expression of genes in human preimplantation embryos. Prenat. Diagn. 18, 1366–1373. Pierce, G. B., Lewellyn, A. L., and Parchment, R. E. (1989). Mechanism of programmed cell death in the blastocyst. Proc. Natl. Acad. Sci. U.S.A. 86, 3654–3658. Polejaeva, I. A., Chen, S. H., Vaught, T. D., Page, R. L., Mullins, J., Ball, S., Dai, Y., Boone, J., Walker, S., Ayares, D. L., Colman, A., and Campbell, K. H. (2000). Cloned pigs produced by nuclear transfer from adult somatic cells. Nature (London) 407, 86–90. Polifka, J. E., Rutledge, J. C., Kimmel, G. L., Dellarco, V., and Generoso, W. M. (1996). Exposure to ethylene oxide during the early zygotic period induces skeletal anomalies in mouse fetuses. Teratology 53, 1–9. Puissant, F., Van Rysselberge, M., Barlow, P., Deweze, J., and Leroy, F. (1987). Embryo scoring as a prognostic tool in IVF treatment. Hum. Reprod. 2, 705–708.

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

189

Rogers, P., and Leeton, J. (2000). Uterine receptivity and embryo transfer. In “Handbook of in Vitro Fertilization” (A. O. Trounson and D. K. Gardner, Eds.), 2nd ed., pp. 499–528. CRC Press, Boca Raton, Florida. Rolstad, B., and Seaman, W. E. (1998). Natural killer cells and recognition of MHC class I molecules: New perspectives and challenges in immunology. Scand. J. Immunol. 47, 412– 425. Rouas-Freiss, N., Goncales, R. M.-B., Menier, C., Dausset, J., and Carosella, E. D. (1997a). Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proc. Natl. Acad. Sci. U.S.A. 94, 11520–11525. Rouas-Freiss, N., Marchal, R. E., Kirzenbaum, M., Dausset, J., and Carosella, E. D. (1997b). The α1 domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: Is HLA-G the public ligand for natural killer cell inhibitory receptors? Proc. Natl. Acad. Sci. U.S.A. 94, 5249–5254. Schultz, R. M. (1999). Blastocyst. In “Encyclopedia of Reproduction” (E. Knobil and J. D. Neill, Eds.), pp. 370–375. Academic Press, San Diego, California. Schultz, R. M., Davis, W., Jr., Stein, P., and Svoboda, P. (1999). Reprogramming of gene expression during preimplantation development. J. Exp. Zool. 285, 276–282. Sellens, M. H., and Jenkinson, E. J. (1975). Permeability of the mouse zona pellucida to immunoglobulin. J. Reprod. Fertil. 42, 153–157. Sheth, B., Fesenko, I., Collins, J. E., Moran, B., Wild, A. E., Anderson, J. M., and Fleming, T. P. (1997). Tight junction assembly during mouse blastocyst formation is regulated by late expression of ZO-1 α+ isoform. Development 124, 2027–2037. Sheth, B., Moran, B., Anderson, J. M., and Fleming, T. P. (2000). Post-translational control of occludin membrane assembly in mouse trophectoderm: A mechanism to regulate timing of tight junction biogenesis and blastocyst formation. Development 127, 831–840. Shiels, P. G., Kind, A. J., Campbell, K. H., Waddington, D., Wilmut, I., Colman, A., and Schnieke, A. E. (1999). Analysis of telomere lengths in cloned sheep. Nature (London) 27, 316–317. Sieh, E., Coluzzi, M. L., Cusella de Angelis, G., Mezzogiorno, A., Floridia, M., Canipari, R., Cossu, G., and Vella, S. (1992). The effects of AZT and DDI on pre- and postimplantation mammalian embryos: An in vivo and in vitro study. AIDS Res. Hum. Retroviruses 8, 639–649. Spanos, S., Becker, D. L., Winston, R. M. L., and Hardy, K. (2000). Anti-apoptotic action of insulin-like growth factor-I during human preimplantation embryo development. Biol. Reprod. 63, 1413–1420. Steuerwald, N., Cohen, J., Herrera, R. J., and Brenner, C. A. (1999). Analysis of gene expression in single oocytes and embryos by real-time rapid cycle fluorescence monitored RT-PCR. Mol. Hum. Reprod. 5, 1034–1039. Steuerwald, N., Barritt, J. A., Adler, R., Malter, H., Schimmel, T., Cohen, J., and Brenner, C. A. (2000a). Quantification of mtDNA in single oocytes, polar bodies and subcellular components by real-time rapid cycle fluorescence monitored PCR. Zygote 8, 209–215. Steuerwald, N., Cohen, J., Herrera, R. J., and Brenner, C. A. (2000b). Quantification of mRNA in single oocytes and embryos by real-time rapid cycle fluorescence monitored RT-PCR. Mol. Hum. Reprod. 6, 448–453. Steuerwald, N., Cohen, J., Herrera, R., Sandalinas, M., and Brenner, C. A. (2001). Association between spindle assembly checkpoint expression and maternal age in human oocytes. Mol. Hum. Reprod. 7, 101–109. Stott, J. J., Bennett, R. E., Warner, C. M., and DiMarzio, C. A. (2001). Three-dimensional imaging with a quadrature tomographic microscope. BiOS2001. SPIE Proc. (in press). Stroynowski, I., and Tabaczewski, P. (1996). Multiple products of class Ib Qa-2 genes: Which ones are functional? Res. Immunol. 147, 290–301. Surani, M. A. (1998). Imprinting and the initiation of gene silencing in the germ line. Cell 93, 309–312.

Textures 2.0

06/12/2001

02:49 PM

190

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

Surani, M. A., Barton, S. C., and Norris, M. L. (1984). Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature (London) 308, 548–550. Svoboda, P., Stein, P., Hayashi, H., and Schultz, R. M. (2000). Selective reduction of dormant maternal mRNAs in mouse oocytes by RNA interference. Development 127, 4147–4156. Takeuchi, T., Ergun, B., Huang, T. H., Rosenwaks, Z., and Palermo, G. D. (1999). A reliable technique of nuclear transplantation for immature mammalian oocytes. Hum. Reprod. 14, 1312–1317. Tam, P. P. (1988). Postimplantation development of mitomycin C-treated mouse blastocyst. Teratology 37, 205–212. Tarin, J. J. (1997). Do the fastest concepti have a shorter life span?. Hum. Reprod. 12, 885–889. Taylor, C. T., and Johnson, P. M. (1996). Complement-binding proteins are strongly expressed by human preimplantation blastocysts and cumulus cells as well as gametes. Mol. Hum. Reprod. 2, 52–59. Thomas, T., Voss, A. K., Petrou, P., and Gruss, P. (2000). The murine gene, Traube, is essential for the growth of preimplantation embryos. Dev. Biol. 227, 324–342. Titenko, N. V. (1977). Preimplantation development of mouse embryos in homo- and heterogeneous crosses. Ontogenez 8, 27–33. Toltzis, P., Mourton, T., and Magnuson, T. (1993). Effect of zidovudine on preimplantation murine embryos. Antimicrob. Agents Chemother. 37, 1610–1613. Trimarchi, J. R., Liu, L., Porterfield, D. M., Smith, P. J., and Keefe, D. L. (2000a). A non-invasive method for measuring preimplantation embryo physiology. Zygote 8, 15–24. Trimarchi, J. R., Liu, L., Porterfield, D. M., Smith, P. J., and Keefe, D. L. (2000b). Oxidative phosphorylation-dependent and -independent oxygen consumption by individual preimplantation mouse embryos. Biol. Reprod. 62, 1866–1874. Trounson, A. O., and Gardner, D. K. (2000). “Handbook of in Vitro Fertilization,” 2nd ed., CRC Press, Boca Raton, Florida. Trounson, A., and Osborn, J. (1993). In vitro fertilization and embryo development. In “Handbook of in Vitro Fertilization” (A. Trounson and D. K. Gardner, Eds.), pp. 57–84. CRC Press, Boca Raton, Florida. Turner, K., and Horobin, R. W. (1997). Permeability of the mouse zona pellucida: A structure-staining-correlation model using coloured probes. J. Reprod. Fertil. 111, 259–265. van der Ven, K., Skrablin, S., Engels, G., and Krebs, D. (1998a). HLA-G polymorphisms and allele frequencies in Caucasians. Hum. Immunol. 59, 302–312. van der Ven, K., Skrablin, S., Ober, C., and Krebs, D. (1998b). HLA-G polymorphisms: Ethnic differences and implications for potential molecule function. Am. J. Reprod. Immunol. 40, 145–157. Van Soom, A., Ysebaert, M. T., and deKruif, A. (1997). Relationship between timing of development, morula morphology, and cell allocation to the inner cell mass and trophectoderm in in vitro-produced bovine embryos. Mol. Reprod. Dev. 47, 47–56. Verbanac, K. M., and Warner, C. M. (1981). Role of the major histocompatibility complex in the timing of early mammalian development. In “Cellular and Molecular Aspects of Implantation” (S. R. Glasser and D. W. Bullock, Eds.), pp. 467–470. Plenum Publishers, New York. Vestweber, D., Ocklind, C., Gossler, A., Odin, P., Obrink, B., and Kemler, R. (1985). Comparison of two cell-adhesion molecules, uvomorulin and cell-CAM 105. Exp. Cell Res. 157, 451–461. Wakayama, T., Shinkai, Y., Tamashiro, K. L., Niida, H., Blanchard, D. C., Blanchard, R. J., Ogura, A., Tanemura, K., Tachibana, M., Perry, A. C., Colgan, D. F., Mombaerts, P., and Yanagimachi, R. (2000). Cloning of mice to six generations. Nature (London) 407, 318–319. Wallace, D. C. (1993). Mitochondrial diseases: Genotype versus phenotype. Trends Genet. 9, 128–133. Wang, J., Paria, B. C., Dey, S. K., and Armant, D. R. (1999). Stage-specific excitation of cannabinoid receptor exhibits differential effects on mouse embryonic development. Biol. Reprod. 60, 839–844.

Textures 2.0

06/12/2001

02:49 PM

Developmental Biology-V. 52

PS057-04.tex

4. Genetic Regulation of Preimplantation Embryo Survival

PS057-04.xml

APserialsv2(2000/12/19)

191

Warner, C. M., and Paschetto, M. G. (2000). Analysis of mRNA levels for the MHC class I-like molecules CD1 and FcRn in preimplantation mouse embryos. Am. J. Reprod. Immunol. 43, 234–239. Warner, C. M., Gollnick, S. O., and Goldbard, S. B. (1987). Linkage of the preimplantation-embryo-development (Ped) gene to the mouse major histocompatibility complex (MHC). Biol. Reprod. 36, 606–610. Warner, C. M., Brownell, M. S., and Ewoldsen, M. A. (1988). Why aren’t embryos immunologically rejected by their mothers? Biol. Reprod. 38, 17–29. Warner, C. M., Brownell, M. S., and Rothschild, M. F. (1991). Analysis of litter size and weight in mice differing in Ped gene phenotype and the Q region of the H-2 complex. J. Reprod. Immunol. 19, 303–313. Warner, C. M., Panda, P., Almquist, C. D., and Xu, Y. (1993). Preferential survival of mice expressing the Qa-2 antigen. J. Reprod. Fertil. 99, 145–147. Warner, C. M., Cao, W., Exley, G. E., McElhinny, A. S., Alikani, M., Cohen, J., Scott, R. T., and Brenner, C. A. (1998a). Genetic regulation of egg and embryo survival. Hum. Reprod. 13, 178–190. Warner, C. M., Exley, G. E., McElhinny, A. S., and Tang, C. (1998b). Genetic regulation of preimplantation mouse embryo survival. J. Exp. Zool. 282, 272–279. Warner, C. M., McElhinny, A. S., Wu, L., Cieluch, C., Ke, X., Cao, W., Tang, C., and Exley, G. E. (1998c). Role of the Ped gene and apoptosis genes in control of preimplantation development. J. Asst. Reprod. Gen. 15, 331–337. Warner, C. M., Tyas, D. A., Goldstein, C., Cohen, J., and Brenner, C. A. (2001). Correlation of genetic polymorphisms in the HLA region with pregnancy outcome after assisted reproduction (in preparation). Wassarman, P. M. (1988). Zona pellucida glycoproteins. Annu. Rev. Biochem. 57, 415–442. Wassarman, P. M., and Mortillo, S. (1991). Structure of the mouse egg extracellular coat, the zona pellucida. Int. Rev. Cytol. 130, 85–110. Wassarman, P., Chen, J., Cohen, N., Litscher, E., Liu, C., Qi, H., and Williams, Z. (1999). Structure and function of the mammalian egg zona pellucida. J. Exp. Zool. 285, 251–258. Watson, A. J. (1992). The cell biology of blastocyst development. Mol. Reprod. Dev. 33, 492–504. Watson, A. J., Westhusin, M. E., De Sousa, P. A., Betts, D. H., and Barcroft, L. C. (1999). Gene expression regulating blastocyst formation. Theriogenology 51, 117–133. Weil, M., Jacobson, M. D., Coles, H. S. R., Davies, T. J., Gardner, R. L., Raff, K. D., and Raff, M. C. (1996). Constitutive expression of the machinery for programmed cell death. J. Cell Biol. 133, 1053–1059. Whitten, W. K., and Biggers, J. D. (1968). Complete development in vitro of the pre-implantation stages of the mouse in a simple chemically defined medium. J. Reprod. Fertil. 17, 399–401. Whitten, W. K., and Dagg, C. P. (1962). Influence of spermatozoa on the cleavage rate of mouse eggs. J. Exp. Zool. 148, 173–183. Wiemer, K. E., Cohen, J., Tucker, M. J., and Godke, R. A. (1998). The application of co-culture in assisted reproduction: 10 years of experience with human embryos. Hum. Reprod. 13, 226– 238. Wilmut, I., Sales, D. I., and Ashworth, C. J. (1986). Maternal and embryonic factors associated with prenatal loss in mammals. J. Reprod. Fertil. 76, 851–864. Wilson, M. E., Sonstegard, T. S., Smith, T. P. L., Fahrenkrug, S. C., and Ford, S. P. (2000). Differential gene expression during elongation in the preimplantation pig embryo. Genesis 26, 9–14. Wu, L., Feng, H., and Warner, C. M. (1999). Identification of two major histocompatibility complex class Ib genes, Q7 and Q9, as the Ped gene in the mouse. Biol. Reprod. 60, 1114–1119. Xu, C., Mao, D., Holers, V. M., Palanca, B., Cheng, A. M., and Molina, H. (2000). A critical role for murine complement regulator Crry in fetomaternal tolerance. Science 287, 498–501.

Textures 2.0

06/12/2001

02:49 PM

192

Developmental Biology-V. 52

PS057-04.tex

PS057-04.xml

APserialsv2(2000/12/19)

Carol M. Warner and Carol A. Brenner

Xu, Y., Jin, P., Mellor, A. L., and Warner, C. M. (1994). Identification of the Ped gene at the molecular level: The Q9 MHC class I transgene converts the Ped slow to the Ped fast phenotype. Biol. Reprod. 51, 695–699. Yamashita, T., Fujii, T., Tokunaga, K., Tadokoro, K., Hamai, Y., Miki, A., Kozuma, S., Juji, T., and Taketani, Y. (1999). Analysis of human leukocyte antigen-G polymorphism including intron 4 in Japanese couples with habitual abortion. Am. J. Reprod. Immunol. 41, 159–163. Yanagimachi, R. (1994). Fertility of mammalian spermatozoa: Its development and relativity. Zygote 2, 371–372. Yang, H. W., Hwang, K. J., Kwon, H. C., Kim, H. S., Choi, K. W., and Oh, K. S. (1998). Detection of reactive oxygen species (ROS) and apoptosis in human fragmented embryos. Hum. Reprod. 13, 998–1002. Young, S. E., Sinclair, K. D., and Wilmut, I. (1998). Large offspring syndrome in cattle and sheep. Rev. Reprod. 3, 155–163. Zhang, J., Wang, C. W., Krey, L., Liu, H., Meng, L., Blaszczyk, A., Adler, A., and Grifo, J. (1999). In vitro maturation of human preovulatory oocytes reconstructed by germinal vesicle transfer. Hum. Reprod. 71, 726–731.

Textures 2.0