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‘Imprinting and Growth Congress’ 2002, London, UK
Placenta (2003), 24, 119–121 doi:10.1053/plac.2002.0892
MEETING REPORT ‘Imprinting and Growth Congress’ 2002, London, UK M. Hembergera, A. Ferguson-Smithb and G. Moorec a Department of Molecular Biology and Biochemistry, University of Calgary, Calgary, Alberta, T2N 4N1, Canada; b Department of Anatomy, University of Cambridge, Cambridge CB2 3DY, UK; c Institute of Reproductive and Developmental Biology, Imperial College, Hammersmith Campus, London W12 0NN, UK
GENOMIC IMPRINTING AND PLACENTAL DEVELOPMENT: IMPLICATIONS FOR FOETAL GROWTH The development of a placenta as an organ of foetal–maternal gas and nutrient exchange is characteristic of eutherian mammals. Mammalian development is also governed by a non-equivalence of the two parental genomes, a phenomenon known as genomic imprinting. It has been proposed that these characteristics are functionally linked, in that genomic imprinting plays a vital role particularly for placental development (Haig, 1993). Consistent with this hypothesis is the finding that alterations in the normal expression of imprinted genes result in growth abnormalities, the majority of which are seen in utero. This is of clinical relevance because of the increased interest in exploring any genetic basis for common problems of pregnancy, including intra-uterine growth restriction and pre-eclampsia. Over the last few years, much progress has been made in unravelling the specific functions of individual imprinted genes and of large imprinted chromosomal regions during placental development. Some of the latest results were reported during the ‘Imprinting and Growth Congress’ held in London from 11–13 April 2002. The first half of the meeting described work that utilized animal models, particularly the mouse, in the study of the functional relationship between imprinted genes and the control of prenatal growth. One of the first genes discovered to be subject to genomic imprinting is the paternally expressed insulin-like growth factor II (Igf2). Igf2 critically controls foetal growth rate, in particular in the second half of gestation when placental function becomes limiting for further embryonic growth (DeChiara et al., 1991; Ferguson-Smith et al., 1991; Sun et al., 1997). A prominent role for Igf2 in the placenta was suggested by the discovery of a placenta-specific promoter (P0) and two placenta-specific exons (U1 and U2) in the 5 -region of the Igf2 gene (Moore et al., 1997). Miguel Constaˆncia (The Babraham Institute, Cambridge) presented work on discerning the function of this placenta-specific Igf2 transcript that is confined to the labyrinthine region of the 0143–4004/02/$-see front matter
murine placenta. Lack of this transcript by deletion of one of the upstream exons (U2) leads to growth restriction of the placenta starting at embryonic day E12. At birth, placentae of U2 mutants are about 70% the size of placentae of littermates with a functional (paternal) Igf2 allele. Interestingly, this growth retardation is within the range of the complete Igf2 knockout suggesting that placental growth is predominantly controlled by the placenta-specific P0-transcript despite the presence of other Igf2 isoforms in the placenta. Onset of embryonic growth restriction is delayed and is detectable only after E16. By investigating the passive and active transport rates of radiolabelled components from the mother to the fetus it was shown that trans-placental passive permeability is decreased whereas active transfer is initially higher in P0 mutant than in wild-type placentae. This enhanced efficiency of the mutant placentae can therefore explain the late onset of foetal growth reduction. The P0 mutant placenta is incapable of compensating for the overall smaller exchange surface only near term. This is the first evidence for action of an imprinted gene in controlling the maternal nutrient supply to the embryo (Constancia et al., 2002). The next step is to analyse the human IGF2 transcripts to see if a similar promotor and specific placental transcript exists. The control of foetal growth by a combination of placental size and nutrient transfer efficacy and the possible roles of insulin-like growth factors and receptors in this system was further emphasized in a presentation by Abigail Fowden (Department of Physiology, University of Cambridge). Comparing effects of Igf1 and Igf2, the Igf2-linked gene H19 as well as the Igf-receptors Igf1r and Igf2r, Igf2 seems to be the only factor that specifically acts on placental growth directly. Although there is a positive correlation between Igf1 serum levels and birth weight (in sheep), administration of Igf1 protein has no general effect but leads to a selective increase in specific organ weights. Apparently, through the regulation of other hormones such as cortisol, Igf1 can modulate placental nutrient transfer rates and regulate foetal growth in relation to the nutrient supply. These reports nicely exemplified the role of insulin-like growth factors in placental development that
120
affect embryonic growth indirectly by controlling nutrient supply. Hence members of the Igf family are crucial growth factors in directing nutrient supply and demand in utero. It is clear that both the placenta and genomic imprinting are important for appropriate foetal development in utero. It is an exciting time in both the genomic imprinting and placental development fields that the two are becoming closely interlinked. Intrauterine growth restriction is an important medical problem and is linked with risk of chronic and serious adult diseases such as heart disease and Type 2 diabetes. It is clear that inheritance of some of these have parent-of-origin associations [Mark McCarthy (Imperial College, London); David Dunger (Paediatrics Department, Cambridge)]. Understanding which genes when inherited from a specific parent control growth and how these genes work will enlighten us to the controlling biochemical pathways and will in the long run give rise to diagnosis and treatment. It is clear that IGF2 is a key player and its expression in the placenta may be controlled by a human equivalent to the P0 promotor or perhaps by other neighbouring sequences. Interestingly, correlations between phenotype and genomic properties of the neighbouring insulin VNTR were reported. In addition to foetal/placental growth factors, establishment of a functional placenta is also critically dependent on the action of cell cycle regulators. p57Kip2/Cdkn1c is an imprinted gene expressed from the maternally inherited allele and its product functions as a negative regulator of cell cycle progression. As presented in the plenary lecture of Jay Cross (University of Calgary, Canada), p57Kip2-mutant mice exhibit foetal overgrowth and an increase of placental weight at term. Being expressed in the labyrinth and spongiotrophoblast (Georgiades et al., 2001; Takahashi et al., 2000; Zhang et al., 1998), p57Kip2-deficiency most evidently causes an overproliferation of the labyrinthine trophoblast layer (Takahashi et al., 2000; Zhang et al., 1998). As a consequence, foetal capillaries are smaller than normal and foetal–maternal nutrient exchange is disrupted due to the increased thickness of the trophoblast barrier. These data, together with results from other gene deletions such as Esx1 (Li & Behringer, 1998), clearly show that placental weight and placental exchange capacity are not necessarily positively correlated, but that cell type composition and spatial arrangement are also crucial for full functionality. All genes described so far in more detail, i.e. Igf1, Igf2 and p57Kip2, are located on distal mouse chromosome 7. However, other imprinted chromosomal regions also have major impacts on placental development. One of the best-studied examples in this respect is mouse chromosome 12, work led and presented by Anne Ferguson-Smith (Department of Anatomy, University of Cambridge). Paternal uniparental disomy (pUPD) of chromosome 12 causes placentomegaly accompanied by morphological anomalies that interfere with normal placental function. Characteristically, pUPD12 placentae exhibit a decreased relative density of foetal capillaries in the labyrinth, accompanied by a separation of the basement membrane and the innermost labyrinth trophoblast layer. In
Placenta (2003), Vol. 24
addition, similar to the observations in p57Kip2-mutant placentae, the trilaminar trophoblast barrier is significantly thickened imposing an interference with nutrient exchange. Interestingly, the analysis of pUPD12 placentae also revealed that foetal placental cells are actively involved in remodelling the maternal vasculature. Maternal spiral arteries normally lack a smooth muscle wall to allow unperturbed blood flow into the labyrinth. This transformation does not occur in the decidual layer of pUPD12 placentae perhaps due to a decreased decidual invasion of zygote derived glycogen cells (Georgiades et al., 2001; Georgiades et al., 2000). Although the imprinted gene(s) on chromosome 12 that cause these severe defects have not been identified yet, the pUPD12 analysis is another clear example of the importance of genomic imprinting for placental development. The striking roles of many imprinted genes for placental development have raised the proposal that genomic imprinting is particularly important for embryonic growth by exerting control over the placenta. This notion is supported by the finding that most imprinted genes are expressed in the placenta (Reik & Walter, 2001), although not necessarily in the trophoblast lineage (Mayer et al., 2000). Interestingly, the reverse correlation also seems to hold true: large-scale analyses conducted and presented by Myriam Hemberger (University of Calgary, Canada) aimed to identify genes expressed and regulated during placental development and revealed a predominant clustering of placenta-expressed genes within imprinted chromosomal domains (Ko et al., 1998) (M. Hemberger, unpublished results). These screens should be very useful to identify genes within imprinted intervals that are clearly associated with placental anomalies, such as mouse chromosomes 12 and proximal chromosome 2. As outlined by Reinald Fundele (Berlin), one explanation for the role of genomic imprinting specifically in placental development is the target function of the placenta in speciation. This function is evident from placental malformations that can constitute a postzygotic barrier against interspecific hybridization. Hybrid dysgenesis genes acting in mammalian speciation typically affect the placenta, overall growth, behaviour and fertility. These sites of action overlap largely with those of imprinted genes and parental origin effects are evident suggesting that imprinting may be involved. However, though manipulating the same targets, the individual strategies to achieve barriers to speciation might be very different even in closely related species. This becomes obvious from studies on interspecific hybrids within the rodent genus Peromyscus and Mus. They both exhibit very similar placental dysplasias (Rogers & Dawson, 1970; Zechner et al., 1996) however, the phenotypical resemblance is caused by divergent molecular mechanisms as revealed by comparing the imprinting status of the paternally expressed gene Peg3 and its interactions with the X-chromosome (Vrana et al., 2000) (R. Fundele, unpublished results). Thus, epigenetic mechanisms apparently have evolved very rapidly in their function in speciation at least in the placenta, an organ that has undergone extremely fast diversification itself. The role of imprinted
Hemberger et al.: ‘Imprinting and Growth Congress’
genes (if any) in this process remains to be elucidated but the parental origin effects observed do suggest a role. If this were the case, this may provide an alternative theory regarding the evolution of imprinting; perhaps to ensure reproductive success within species boundaries. In summarizing the contributions of these various fields of interest it is evident that placental development and genomic imprinting are intricately linked. Further analysis of the specific functions of imprinted genes in the placenta is therefore essential to gain a better understanding of the development of this organ as well as of the variety of malformations that can severely affect both maternal and foetal health.
REFERENCES Constaˆncia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C & Reik W (2002) Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature, 417, 945–948. DeChiara TM, Robertson EJ & Efstratiadis A (1991) Parental imprinting of the mouse insulin-like growth factor II gene. Cell, 64, 849–859. Ferguson-Smith AC, Cattanach BM, Barton SC, Beechey CV & Surani MA (1991) Embryological and molecular investigations of parental imprinting on mouse chromosome 7. Nature, 351, 667–670. Georgiades P, Watkins M, Burton GJ & Ferguson-Smith AC (2001) Roles for genomic imprinting and the zygotic genome in placental development. Proc Natl Acad Sci U S A, 98, 4522–4527. Georgiades P, Watkins M, Surani MA & Ferguson-Smith AC (2000) Parental origin-specific developmental defects in mice with uniparental disomy for chromosome 12. Development, 127, 4719–4728. Haig D (1993) Genetic conflicts in human pregnancy. Q Rev Biol, 68, 495–532.
121 Ko MS, Threat TA, Wang X, Horton JH, Cui Y, Pryor E, Paris J, Wells-Smith J, Kitchen JR, Rowe LB, Eppig J, Satoh T, Brant L, Fujiwara H, Yotsumoto S & Nakashima H (1998) Genome-wide mapping of unselected transcripts from extraembryonic tissue of 7.5-day mouse embryos reveals enrichment in the t-complex and under-representation on the X chromosome. Hum Mol Genet, 7, 1967–1978. Li Y & Behringer RR (1998) Esx1 is an X-chromosome-imprinted regulator of placental development and fetal growth. Nat Genet, 20, 309–311. Mayer W, Hemberger M, Frank HG, Grummer R, Winterhager E, Kaufmann P & Fundele R (2000) Expression of the imprinted genes MEST/Mest in human and murine placenta suggests a role in angiogenesis. Dev Dyn, 217, 1–10. Moore T, Constancia M, Zubair M, Bailleul B, Feil R, Sasaki H & Reik W (1997) Multiple imprinted sense and antisense transcripts, differential methylation and tandem repeats in a putative imprinting control region upstream of mouse Igf2. Proc Natl Acad Sci U S A, 94, 12509–12514. Reik W & Walter J (2001) Genomic imprinting: parental influence on the genome. Nat Rev Genet, 2, 21–32. Rogers JF & Dawson WD (1970) Foetal and placental size in a Peromyscus species cross. J Reprod Fertil, 21, 255–262. Sun FL, Dean WL, Kelsey G, Allen ND & Reik W (1997) Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome. Nature, 389, 809–815. Takahashi K, Kobayashi T & Kanayama N (2000) p57(Kip2) regulates the proper development of labyrinthine and spongiotrophoblasts. Mol Hum Reprod, 6, 1019–1025. Vrana PB, Fossella JA, Matteson P, del Rio T, O’Neill MJ & Tilghman SM (2000) Genetic and epigenetic incompatibilities underlie hybrid dysgenesis in Peromyscus. Nat Genet, 25, 120–124. Zechner U, Reule M, Orth A, Bonhomme F, Strack B, Guenet J-L, Hameister H & Fundele R (1996) An X-chromosome linked locus contributes to abnormal placental development in mouse interspecific hybrids. Nat Genet, 12, 398–403. Zhang P, Wong C, DePinho RA, Harper JW & Elledge SJ (1998) Cooperation between the cdk inhibitors p27(KIP1) and p57(KIP2) in the control of tissue growth and development. Genes Dev, 12, 3162–3167.
MEETING REPORT ‘Imprinting and Growth Congress’ 2002, London, UK M. Hembergera, A. Ferguson-Smithb and G. Moorec a Department of Molecular Biology and Biochemistry, University of Calgary, Calgary, Alberta, T2N 4N1, Canada; b Department of Anatomy, University of Cambridge, Cambridge CB2 3DY, UK; c Institute of Reproductive and Developmental Biology, Imperial College, Hammersmith Campus, London W12 0NN, UK
GENOMIC IMPRINTING AND PLACENTAL DEVELOPMENT: IMPLICATIONS FOR FOETAL GROWTH The development of a placenta as an organ of foetal–maternal gas and nutrient exchange is characteristic of eutherian mammals. Mammalian development is also governed by a non-equivalence of the two parental genomes, a phenomenon known as genomic imprinting. It has been proposed that these characteristics are functionally linked, in that genomic imprinting plays a vital role particularly for placental development (Haig, 1993). Consistent with this hypothesis is the finding that alterations in the normal expression of imprinted genes result in growth abnormalities, the majority of which are seen in utero. This is of clinical relevance because of the increased interest in exploring any genetic basis for common problems of pregnancy, including intra-uterine growth restriction and pre-eclampsia. Over the last few years, much progress has been made in unravelling the specific functions of individual imprinted genes and of large imprinted chromosomal regions during placental development. Some of the latest results were reported during the ‘Imprinting and Growth Congress’ held in London from 11–13 April 2002. The first half of the meeting described work that utilized animal models, particularly the mouse, in the study of the functional relationship between imprinted genes and the control of prenatal growth. One of the first genes discovered to be subject to genomic imprinting is the paternally expressed insulin-like growth factor II (Igf2). Igf2 critically controls foetal growth rate, in particular in the second half of gestation when placental function becomes limiting for further embryonic growth (DeChiara et al., 1991; Ferguson-Smith et al., 1991; Sun et al., 1997). A prominent role for Igf2 in the placenta was suggested by the discovery of a placenta-specific promoter (P0) and two placenta-specific exons (U1 and U2) in the 5 -region of the Igf2 gene (Moore et al., 1997). Miguel Constaˆncia (The Babraham Institute, Cambridge) presented work on discerning the function of this placenta-specific Igf2 transcript that is confined to the labyrinthine region of the 0143–4004/02/$-see front matter
murine placenta. Lack of this transcript by deletion of one of the upstream exons (U2) leads to growth restriction of the placenta starting at embryonic day E12. At birth, placentae of U2 mutants are about 70% the size of placentae of littermates with a functional (paternal) Igf2 allele. Interestingly, this growth retardation is within the range of the complete Igf2 knockout suggesting that placental growth is predominantly controlled by the placenta-specific P0-transcript despite the presence of other Igf2 isoforms in the placenta. Onset of embryonic growth restriction is delayed and is detectable only after E16. By investigating the passive and active transport rates of radiolabelled components from the mother to the fetus it was shown that trans-placental passive permeability is decreased whereas active transfer is initially higher in P0 mutant than in wild-type placentae. This enhanced efficiency of the mutant placentae can therefore explain the late onset of foetal growth reduction. The P0 mutant placenta is incapable of compensating for the overall smaller exchange surface only near term. This is the first evidence for action of an imprinted gene in controlling the maternal nutrient supply to the embryo (Constancia et al., 2002). The next step is to analyse the human IGF2 transcripts to see if a similar promotor and specific placental transcript exists. The control of foetal growth by a combination of placental size and nutrient transfer efficacy and the possible roles of insulin-like growth factors and receptors in this system was further emphasized in a presentation by Abigail Fowden (Department of Physiology, University of Cambridge). Comparing effects of Igf1 and Igf2, the Igf2-linked gene H19 as well as the Igf-receptors Igf1r and Igf2r, Igf2 seems to be the only factor that specifically acts on placental growth directly. Although there is a positive correlation between Igf1 serum levels and birth weight (in sheep), administration of Igf1 protein has no general effect but leads to a selective increase in specific organ weights. Apparently, through the regulation of other hormones such as cortisol, Igf1 can modulate placental nutrient transfer rates and regulate foetal growth in relation to the nutrient supply. These reports nicely exemplified the role of insulin-like growth factors in placental development that
120
affect embryonic growth indirectly by controlling nutrient supply. Hence members of the Igf family are crucial growth factors in directing nutrient supply and demand in utero. It is clear that both the placenta and genomic imprinting are important for appropriate foetal development in utero. It is an exciting time in both the genomic imprinting and placental development fields that the two are becoming closely interlinked. Intrauterine growth restriction is an important medical problem and is linked with risk of chronic and serious adult diseases such as heart disease and Type 2 diabetes. It is clear that inheritance of some of these have parent-of-origin associations [Mark McCarthy (Imperial College, London); David Dunger (Paediatrics Department, Cambridge)]. Understanding which genes when inherited from a specific parent control growth and how these genes work will enlighten us to the controlling biochemical pathways and will in the long run give rise to diagnosis and treatment. It is clear that IGF2 is a key player and its expression in the placenta may be controlled by a human equivalent to the P0 promotor or perhaps by other neighbouring sequences. Interestingly, correlations between phenotype and genomic properties of the neighbouring insulin VNTR were reported. In addition to foetal/placental growth factors, establishment of a functional placenta is also critically dependent on the action of cell cycle regulators. p57Kip2/Cdkn1c is an imprinted gene expressed from the maternally inherited allele and its product functions as a negative regulator of cell cycle progression. As presented in the plenary lecture of Jay Cross (University of Calgary, Canada), p57Kip2-mutant mice exhibit foetal overgrowth and an increase of placental weight at term. Being expressed in the labyrinth and spongiotrophoblast (Georgiades et al., 2001; Takahashi et al., 2000; Zhang et al., 1998), p57Kip2-deficiency most evidently causes an overproliferation of the labyrinthine trophoblast layer (Takahashi et al., 2000; Zhang et al., 1998). As a consequence, foetal capillaries are smaller than normal and foetal–maternal nutrient exchange is disrupted due to the increased thickness of the trophoblast barrier. These data, together with results from other gene deletions such as Esx1 (Li & Behringer, 1998), clearly show that placental weight and placental exchange capacity are not necessarily positively correlated, but that cell type composition and spatial arrangement are also crucial for full functionality. All genes described so far in more detail, i.e. Igf1, Igf2 and p57Kip2, are located on distal mouse chromosome 7. However, other imprinted chromosomal regions also have major impacts on placental development. One of the best-studied examples in this respect is mouse chromosome 12, work led and presented by Anne Ferguson-Smith (Department of Anatomy, University of Cambridge). Paternal uniparental disomy (pUPD) of chromosome 12 causes placentomegaly accompanied by morphological anomalies that interfere with normal placental function. Characteristically, pUPD12 placentae exhibit a decreased relative density of foetal capillaries in the labyrinth, accompanied by a separation of the basement membrane and the innermost labyrinth trophoblast layer. In
Placenta (2003), Vol. 24
addition, similar to the observations in p57Kip2-mutant placentae, the trilaminar trophoblast barrier is significantly thickened imposing an interference with nutrient exchange. Interestingly, the analysis of pUPD12 placentae also revealed that foetal placental cells are actively involved in remodelling the maternal vasculature. Maternal spiral arteries normally lack a smooth muscle wall to allow unperturbed blood flow into the labyrinth. This transformation does not occur in the decidual layer of pUPD12 placentae perhaps due to a decreased decidual invasion of zygote derived glycogen cells (Georgiades et al., 2001; Georgiades et al., 2000). Although the imprinted gene(s) on chromosome 12 that cause these severe defects have not been identified yet, the pUPD12 analysis is another clear example of the importance of genomic imprinting for placental development. The striking roles of many imprinted genes for placental development have raised the proposal that genomic imprinting is particularly important for embryonic growth by exerting control over the placenta. This notion is supported by the finding that most imprinted genes are expressed in the placenta (Reik & Walter, 2001), although not necessarily in the trophoblast lineage (Mayer et al., 2000). Interestingly, the reverse correlation also seems to hold true: large-scale analyses conducted and presented by Myriam Hemberger (University of Calgary, Canada) aimed to identify genes expressed and regulated during placental development and revealed a predominant clustering of placenta-expressed genes within imprinted chromosomal domains (Ko et al., 1998) (M. Hemberger, unpublished results). These screens should be very useful to identify genes within imprinted intervals that are clearly associated with placental anomalies, such as mouse chromosomes 12 and proximal chromosome 2. As outlined by Reinald Fundele (Berlin), one explanation for the role of genomic imprinting specifically in placental development is the target function of the placenta in speciation. This function is evident from placental malformations that can constitute a postzygotic barrier against interspecific hybridization. Hybrid dysgenesis genes acting in mammalian speciation typically affect the placenta, overall growth, behaviour and fertility. These sites of action overlap largely with those of imprinted genes and parental origin effects are evident suggesting that imprinting may be involved. However, though manipulating the same targets, the individual strategies to achieve barriers to speciation might be very different even in closely related species. This becomes obvious from studies on interspecific hybrids within the rodent genus Peromyscus and Mus. They both exhibit very similar placental dysplasias (Rogers & Dawson, 1970; Zechner et al., 1996) however, the phenotypical resemblance is caused by divergent molecular mechanisms as revealed by comparing the imprinting status of the paternally expressed gene Peg3 and its interactions with the X-chromosome (Vrana et al., 2000) (R. Fundele, unpublished results). Thus, epigenetic mechanisms apparently have evolved very rapidly in their function in speciation at least in the placenta, an organ that has undergone extremely fast diversification itself. The role of imprinted
Hemberger et al.: ‘Imprinting and Growth Congress’
genes (if any) in this process remains to be elucidated but the parental origin effects observed do suggest a role. If this were the case, this may provide an alternative theory regarding the evolution of imprinting; perhaps to ensure reproductive success within species boundaries. In summarizing the contributions of these various fields of interest it is evident that placental development and genomic imprinting are intricately linked. Further analysis of the specific functions of imprinted genes in the placenta is therefore essential to gain a better understanding of the development of this organ as well as of the variety of malformations that can severely affect both maternal and foetal health.
REFERENCES Constaˆncia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C & Reik W (2002) Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature, 417, 945–948. DeChiara TM, Robertson EJ & Efstratiadis A (1991) Parental imprinting of the mouse insulin-like growth factor II gene. Cell, 64, 849–859. Ferguson-Smith AC, Cattanach BM, Barton SC, Beechey CV & Surani MA (1991) Embryological and molecular investigations of parental imprinting on mouse chromosome 7. Nature, 351, 667–670. Georgiades P, Watkins M, Burton GJ & Ferguson-Smith AC (2001) Roles for genomic imprinting and the zygotic genome in placental development. Proc Natl Acad Sci U S A, 98, 4522–4527. Georgiades P, Watkins M, Surani MA & Ferguson-Smith AC (2000) Parental origin-specific developmental defects in mice with uniparental disomy for chromosome 12. Development, 127, 4719–4728. Haig D (1993) Genetic conflicts in human pregnancy. Q Rev Biol, 68, 495–532.
121 Ko MS, Threat TA, Wang X, Horton JH, Cui Y, Pryor E, Paris J, Wells-Smith J, Kitchen JR, Rowe LB, Eppig J, Satoh T, Brant L, Fujiwara H, Yotsumoto S & Nakashima H (1998) Genome-wide mapping of unselected transcripts from extraembryonic tissue of 7.5-day mouse embryos reveals enrichment in the t-complex and under-representation on the X chromosome. Hum Mol Genet, 7, 1967–1978. Li Y & Behringer RR (1998) Esx1 is an X-chromosome-imprinted regulator of placental development and fetal growth. Nat Genet, 20, 309–311. Mayer W, Hemberger M, Frank HG, Grummer R, Winterhager E, Kaufmann P & Fundele R (2000) Expression of the imprinted genes MEST/Mest in human and murine placenta suggests a role in angiogenesis. Dev Dyn, 217, 1–10. Moore T, Constancia M, Zubair M, Bailleul B, Feil R, Sasaki H & Reik W (1997) Multiple imprinted sense and antisense transcripts, differential methylation and tandem repeats in a putative imprinting control region upstream of mouse Igf2. Proc Natl Acad Sci U S A, 94, 12509–12514. Reik W & Walter J (2001) Genomic imprinting: parental influence on the genome. Nat Rev Genet, 2, 21–32. Rogers JF & Dawson WD (1970) Foetal and placental size in a Peromyscus species cross. J Reprod Fertil, 21, 255–262. Sun FL, Dean WL, Kelsey G, Allen ND & Reik W (1997) Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome. Nature, 389, 809–815. Takahashi K, Kobayashi T & Kanayama N (2000) p57(Kip2) regulates the proper development of labyrinthine and spongiotrophoblasts. Mol Hum Reprod, 6, 1019–1025. Vrana PB, Fossella JA, Matteson P, del Rio T, O’Neill MJ & Tilghman SM (2000) Genetic and epigenetic incompatibilities underlie hybrid dysgenesis in Peromyscus. Nat Genet, 25, 120–124. Zechner U, Reule M, Orth A, Bonhomme F, Strack B, Guenet J-L, Hameister H & Fundele R (1996) An X-chromosome linked locus contributes to abnormal placental development in mouse interspecific hybrids. Nat Genet, 12, 398–403. Zhang P, Wong C, DePinho RA, Harper JW & Elledge SJ (1998) Cooperation between the cdk inhibitors p27(KIP1) and p57(KIP2) in the control of tissue growth and development. Genes Dev, 12, 3162–3167.