- Email: [email protected]
The fetal and adult adrenal cortex
Molecular and Cellular Endocrinology 336 (2011) 193–197
Contents lists available at ScienceDirect
Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce
Review
The fetal and adult adrenal cortex Ken-ichirou Morohashi a,∗ , Mohamad Zubair b a b
Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan Department of Internal Medicine, Division of Metabolism Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109-2200, USA
a r t i c l e
i n f o
Article history: Received 2 October 2010 Received in revised form 23 November 2010 Accepted 23 November 2010 Keywords: Ad4BP/SF-1 Adrenal cortex Steroid hormone Enhancer Fetal adrenal
a b s t r a c t The orphan nuclear receptor AD4BP/SF-1 (adrenal-4-binding protein/steroidogenic factor-1 (NR5A1)) is essential for the proper development and function of reproductive and steroidogenic tissues. Although the expression of Ad4BP/Sf-1 is specific for those tissues, the mechanisms underlying this tissue-specific expression remain unknown. Our transgenic studies have identified the tissue-specific enhancers for the fetal adrenal cortex, ventromedial hypothalamus, and pituitary in Ad4BP/Sf-1 gene. The adrenal cortex forms morphologically distinct compartments, the inner (fetal) and outer (definitive or adult) zones. Despite considerable effort, the mechanisms that mediate the differential development of the fetal and adult adrenal cortex remain incompletely understood. It remained controversial whether a true fetal type adrenal cortex is present in mice, and this argument was complicated by the postnatal development of the so-called X-zone. Using transgenic mice with lacZ driven by the fetal adrenal enhancer (FAdE), we clearly identified a fetal adrenal cortex in mice, and the X-zone is the fetal adrenal cells accumulated at the juxtamedullary region after birth. We combined the FAdE with the Cre/loxP system to trace cell lineages in which the FAdE was active at some stage in development. These lineage tracing studies establish definitively that the adult cortex derives from precursor cells in the fetal cortex in which the FAdE was activated before the organization into two distinct zones. The potential of these fetal adrenocortical cells to enter the pathway that eventuate in cells of the adult cortex disappeared by E14.5. Thus, these studies demonstrate a direct link between the fetal and adult cortex involving a transition that must occur before a specific stage of development. © 2010 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Identification of fetal adrenal enhancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Correlation of fetal zone and X-zone in the developing mouse adrenal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lineage tracing of the fetal adrenal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Temporal window in which FAdE-active cells can contribute to the adult adrenal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The orphan nuclear receptor, AD4BP/SF-1 (adrenal 4 binding protein/steroidogenic factor-1), has been extensively studied in relation to its key function in steroidogenic gene regulation. Early
Abbreviations: Ad4BP/SF-1, adrernal 4 binding protein/steroidogenic factor-1; FAdE, fetal adrenal enhancer; EGFP, enhanced green fluorescence protein; AGP, adreno-gonad primordium. ∗ Corresponding author. Tel.: +81 92 642 6180; fax: +81 92 642 6181. E-mail address: [email protected] (K.-i. Morohashi). 0303-7207/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2010.11.026
193 194 195 195 196 196 196
studies focused on the transcriptional activity in certain cell types located in the gonads (testis and ovary) and adrenocortical cells. However, gene disruption studies have definitively revealed that Ad4BP/Sf-1 not only functions as a steroidogenic gene regulator, but also functions as an important trophic factor required for establishing and/or maintaining steroidogenic tissues (Luo et al., 1994). Furthermore, expression of the Ad4BP/Sf-1 gene has been detected in the ventromedial hypothalamus (VMH) and the pituitary gonadotrophs (Ingraham et al., 1994; Shinoda et al., 1995; Sadovsky et al., 1995). In addition to its function as a trophic factor in steroidogenesis, Ad4BP/Sf-1 is also essential for the establishment of the VMH and pituitary gonadotrophs. Ad4BP/Sf-1 has also been
194
K.-i. Morohashi, M. Zubair / Molecular and Cellular Endocrinology 336 (2011) 193–197
identified in the spleen (Morohashi et al., 1999; Katoh-Fukui et al., 2005). The phenotype of Ad4BP/Sf-1 KO mice has clearly demonstrated that mechanisms which enable tissue-specific gene expression are critical for the development of those tissues. This regulatory mechanism for Ad4BP/Sf-1 gene expression was studied with cultured cells using the 5 upstream region of the gene. However, based on the results of our own studies of the of the Ad4BP/Sf-1 promoter (Nomura et al., 1995, 1996), we predicted that tissue-specific expression of the gene is regulated not only by the 5 upstream region but tissue-specific enhancers which had been unidentified yet. Therefore, we started to identify the tissue-specific enhancers of the Ad4BP/Sf-1 gene using transgenic (Tg) mouse assays. Partially digested mouse genomic DNA fragments were inserted into a modified cosmid vector containing the 5 upstream region of the gene and EGFP or bacterial lacZ reporter gene. Cosmid clones carrying DNA fragments of the Ad4BP/Sf-1 gene locus were directly subjected to Tg assays. From these, a clone was obtained, which had the potential to induce reporter gene expression in the fetal adrenal cortex (Zubair et al., 2006), ventral diencephalon (the future VMH) (Shima et al., 2005), and Rathke’s pouch (pituitary anlage) (Shima et al., 2008). Thus, in consequence, we localized the enhancer sequences for the fetal adrenal cortex in the fourth intron and for the VMH and pituitary enhancers in the sixth intron. Interestingly, these sequences are conserved among animal species (Fig. 1). 2. Identification of fetal adrenal enhancer Using Tg mouse lines, we characterized the activity of the fetal adrenal-specific enhancer (FAdE). LacZ reporter expression was observed at the medial side of the urogenital ridges at E10.5. The
Fig. 1. Localization of enhancers for fetal adrenal cortex, VMH, and pituitary gonadotroph. The tissue-specific enhancers of Ad4BP/SF-1 gene were localized within the fourth and sixth introns by transgenic mouse assays. All enhancer regions contained multiple sequences conserved among animal species. They are the consensus binding sequences for Ad4BP/SF-1 and Hox/Pbx/Prep in the fetal adrenal enhancer, a consensus binding sequence for Homeo box protein for the VMH enhancer, and a consensus binding sequence for Pitx2 in the pituitary enhancer. The activities of all these sites are lost when mutations are introduced.
results of our previous studies demonstrated that the gonad and adrenal cortex form a single cell group, the adreno-gonad primordium (AGP) (Morohashi, 1997). Cross-sections of rat fetuses (Hatano et al., 1994, 1996) and chick embryos (Yoshioka et al., 2005) revealed that AGP localizes from the coelomic epithelium (ventral domain) in the area proximal to the dorsal aorta (dorsal domain) as a single and AD4BP/SF-1 positive cell population (Fig. 2). When the Tg mouse fetuses stained with lacZ were cross-sectioned, the
Fig. 2. Schematic presentation of early adrenal and gonadal development. (A) AD4BP/SF-1 is the marker protein of the adrenal cortex and gonad from the early stage of tissue development. In our previous studies, we found that the adrenal primordium (AP) and gonad primordium (GP) formed a single AD4BP/SF-1 positive cell population. Thus, we termed the AD4BP/SF-1 positive cells the adreno-gonad primordium (AGP). While these cells were all immunoreactive for AD4BP/SF-1, it was not known if these cells used the same enhancer. However, our transgenic studies demonstrated that FAdE was activated in the dorsal (dark grey with an arrow labeled with AP) but not in the ventral region (light grey with an arrow labeled with GP) at E11.5. This observation indicated that the AP and GP were differentiated at E11.5 even though they formed a single cell population that was AD4BP/SF-1 positive. Thereafter, at E12.5 they were morphologically divided into two subpopulations, AP and GP. (B) Adrenal cortical and gonadal somatic cells (Sertoli and Leydig cells) are derived from the same progenitor cells (AGP). They give rise to two precursor cells for the adrenal cortex (AP) and gonad, respectively. FAdE is activated in the AP cells, but not in the gonadal precursor cells. Soon after, some cells in the AP change the usage of the enhancer from FAdE to an as of yet unidentified adult adrenal enhancer.
K.-i. Morohashi, M. Zubair / Molecular and Cellular Endocrinology 336 (2011) 193–197
195
Fig. 3. Transition of the adrenal cortex from fetal to adult. The transition processes in a mouse and human are illustrated. During the fetal stage, the adrenal cortex consists of an outer definitive adult zone (light grey) and an inner fetal zone (dark grey). Thereafter, the fetal zone becomes thinner while the adult zone becomes thicker during the fetal age in the mouse and after birth in humans. Interestingly, the fetal cells sporadically distribute in the medulla afterbirth (neonatal stage) in the mouse, and thereafter form the inner cell layer again. This newly formed cell layer disappears soon at the pubertal stage in males but persists so that it is present until first pregnancy in females.
lacZ signal was clearly localized within the area corresponding to the dorsal domain of the AGP (Zubair et al., 2006). This lacZ expression strongly suggested that the FAdE was used in the dorsal cells while the other unknown enhancer was activated within the ventral cells. Subsequently, AGP divided into two separate primordia; the adrenal primordium (AP) and the gonadal primordium (GP). LacZ activity became unexpectedly weak at E17.5. A crosssectional analysis revealed a small population of lacZ-positive cortical cells proximal to the medulla; all other cells remained inactive and this staining pattern was maintained until the neonatal period. However, by postnatal day 12 (P12), lacZ signals were detected sporadically throughout the medulla and thereafter accumulated again around the medulla. By P35, lacZ-expressing cells were mostly absent from the male tissue; but, although decreased in quantity, lacZ-positive cells persisted in females at the innermost cortical layer until P53. These cells completely regressed during the first pregnancy (Fig. 3). This expression profile indicates that the enhancer was unable to drive transgenetic expression in the adult adrenal cortex and suggests that another unidentified adult adrenal enhancer would drive gene expression in the adult. Therefore, there appear to be different systems for gene regulation within the fetal and adult adrenal cortex. 3. Correlation of fetal zone and X-zone in the developing mouse adrenal cortex
birth (Masui and Tamura, 1926; Howard-Miller, 1927). This particular layer disappears during puberty in male mice (Howard-Miller, 1927), but persists in female mice until the first pregnancy (Holmes and Dickson, 1971). Our Tg study with FAdE indicated that the fetal adrenal cortex was present in males until puberty and remained present in females until after sexual maturation. Moreover, lacZ expression in females completely disappeared after the first pregnancy (Fig. 3). This expression pattern was remarkably similar to the kinetics of X-zone regression, strongly implying that the lacZ expressing cells (fetal adrenal cortex) comprise the X-zone. However, the Xzone is believed to emerge after birth. This discrepancy may arise from the unique distribution of lacZ-positive fetal adrenal cells during the neonatal period. Shortly after birth, lacZ positive cells are distributed sporadically in the medulla, and thereafter, they accumulate in the juxtamedullary region, where the development of the develop X-zone is believed to occur (Hirokawa and Ishikawa, 1974). Previous studies examining the X-zone have utilized structural and histological observations rather than studying marker gene expression and this has made it difficult to establish the origins of the X-zone. Overall, our results demonstrate that the fetal adrenal zone is present in the mouse fetus and is maintained after birth as X-zone cells. Furthermore, we have also observed that the development of the mouse adrenal gland appears to be similar to that of other mammals. 4. Lineage tracing of the fetal adrenal cortex
The fetal adrenal cortices of many mammalian species consists of two distinct cell groups; small and tightly packed outer cells which form the adult zone, and the larger and irregularly aligned inner cells forming the fetal zone (Keegan and Hammer, 2002). During gestation, the fetal zone is enlarged and synthesizes steroids, while the adult zone remains undifferentiated. Following birth, the fetal zone regresses while the adult zone increases in size. Although both the rat and mouse fetal adrenal cortices develop the two distinct layers as with other mammalian species, their adrenal glands lack a ‘true’ fetal zone (Lanman, 1953). Rather, the fetal zone degeneration and growth of the adult zone starts in the late fetal stage of these rodents. Additionally, the mouse adrenal cortex develops a unique islet of eosinophilic cells, the so-called X-zone, after
The fetal adrenal cortex of many mammalian species consists of adult/definitive and fetal zones of which origins remain poorly understood. Morphological studies have led to the proposal of three different models to explain the origins of the adrenal cortex. One model proposes that the adult zone may be derived from the coelomic epithelia following the migration of the cells that form the fetal zone (Uotila, 1940). An alternative model is that the fetal and adult zones may be derived simultaneously from discrete populations of coelomic epithelial cells (Crowder, 1957). Both these models postulate that the cells comprising the fetal and adult zones are pre-determined in their cell fates when they develop from the coelomic epithelia. In contrast, the third model postulates that both
196
K.-i. Morohashi, M. Zubair / Molecular and Cellular Endocrinology 336 (2011) 193–197
zones differentiate from a single progenitor population that subsequently differentiates into distinct fetal and adult zones. To address which model is accurate, fetal adrenal cells were traced using Tg mice in which Cre recombinase was expressed by FAdE (Zubair et al., 2008). Tg mice were mated with ROSA26R reporter mice (Soriano, 1999) to trace the lacZ-positive fetal adrenal cells. LacZ expression was examined in the Cre/ROSA Tg male mice until 2 months after birth. As mentioned above, lacZ staining persisted in the inner part of the adrenal cortex (corresponding to the X zone) of the Tg mice, in which lacZ was driven by FAdE (normal Tg mice), but disappeared in the adult adrenal. By contrast, lacZ was clearly detectable not only in the fetal adrenal cortex but throughout the adult cortex of Cre/ROSA Tg mice, clearly indicating that the adult adrenal cortex is derived from fetal adrenal cells.
5. Temporal window in which FAdE-active cells can contribute to the adult adrenal cortex The next question that arose to us was whether or not fetal adrenal cells of all stages have the ability to differentiate into the adult adrenal cortex. To address this question, we generated transgenic mice with Cre-ERT2 expression under the control of FAdE (Zubair et al., 2008). Moreover, the Cre-ERT2 fusion protein is activated only in the presence of tamoxifen. Thus, Cre-mediated recombination should occur only when Tg mice are treated with tamoxifen. Tamoxifen was administered at E11.5, E14.5, or P6, and the mice were examined two months after birth. Most adult cortical cells of the mice treated at E11.5 expressed lacZ. However, if tamoxifen treatment was delayed until E14.5 or postnatal day 6, the cells that retained lacZ expression were not present in the adult adrenal cortex. These results demonstrate that fetal adrenal cells are capable of differentiating into adult adrenal cells and the ability disappeared by E14.5. The cell lineage studies above strongly support the third model, as they show that the adult zone is derived from the early stages of the fetal adrenal cortical zone. Interestingly, the capacity of these precursors to differentiate into the adult zone largely disappears by E14.5. Indeed, the adrenal primordia of Ad4BP–lacZ–FAdE Tg mice at E11.5 to E12.5 contain variable amounts of cells that weakly express lacZ, which presumably are in the process of extinguishing the FAdE activation. By E14.5, these cells preferentially localize in a thin layer at the surface of the cortex possibly to form the adult cortical zone. Importantly, we propose that the transition simultaneously involves a change in enhancer usage in the Ad4BP/Sf-1 locus from the FAdE to an adult adrenal enhancer, which remains to be identified. Further research is required to determine what induces such cell fate change from the fetal to adult cells; or what induces change of enhancer usage from FAdE to an unidentified adult adrenal enhancer remains. These studies will help us to figure out the whole process of adrenal development. In the series of studies, we demonstrated that Ad4BP/SF-1 gene is regulated by multiple tissue-specific enhancers. Since these enhancers are capable of activating any gene expression in tissuespecific manners, we generated Tg mouse lines in which GFP or Cre is expressed under the control of FAdE. Investigation of the Tg mouse lines clarified two issues. One of them is that X-zone cells of postnatal adrenal glands are the descendents of the fetal adrenal cortex. The other of them is that adult adrenal cortex is derived from fetal adrenal cortex, and the fetal adrenal cortex before E14.5 retains its ability to differentiate into adult adrenal cortex. In addition to these findings, we recently identified fetal Leydig enhancer, and established Tg mouse lines as we did with FAdE. As I mentioned previously, the fetal adrenal cortex and testicular Leydig cells have been discussed to be derived from same primordial cells. In order
to figure out the whole view of the steroidogenic cell development, the mouse lines generated using FAdE and fetal Leydig enhancer would be powerful tools.
Acknowledgments As mentioned above, the tissue-specific enhancers can potentially induce expression of any gene in a tissue-specific manner. Therefore, the enhancers are powerful tools to study and understand the mechanisms underlying tissue development. We started our collaborative studies with Keith by using the FAdE, and our studies were subsequently published in 2008 (Zubair et al., 2008) and 2009 (Zubair et al., 2009). The time we spent with Keith in preparing the manuscripts is a precious personal memory. My career (Ken Morohashi) as a scientist commenced with reading his papers describing steroidogenic gene regulation. I found these to be an excellent and interesting read (Handler et al., 1988; Mouw et al., 1989; Rice et al., 1989, 1990a,b; Bogerd et al., 1990). Since the factor he identified was identical with what I identified, I was able to work with him in the same field for the last 20 years. We attended some of the same meetings, such as series of Adrenal Conference and Molecular Steroidogenesis. It was my pleasure to hear of his various successes and hopefully for him to hear of mine. I believe that his presence has helped me improve the quality of my science, and also created an exciting and productive life as a scientist. I greatly appreciate not only his outstanding contribution to the medical and biological fields but also his fairness, friendship, and warm hospitality.
References Bogerd, A.M., Franklin, A., Rice, D.A., Schimmer, B.P., Parker, K.L., 1990. Identification and characterization of two upstream elements that regulate adrenocortical expression of steroid 11 beta-hydroxylase. Molecular Endocrinology 4, 845–850. Crowder, R., 1957. The development of the adrenal gland in man, with special reference to origin and ultimate location of cell types and evidence in favor of the “cell migration” theory. Contemporary Embryology 251, 195–209. Handler, J.D., Schimmer, B.P., Flynn, T.R., Szyf, M., Seidman, J.G., Parker, K.L., 1988. An enhancer element and a functional cyclic AMP-dependent protein kinase are required for expression of adrenocortical 21-hydroxylase. The Journal of Biological Chemistry 263, 13068–13073. Hatano, O., Takayama, K., Imai, T., Waterman, M.R., Takakusu, A., Omura, T., Morohashi, K., 1994. Sex-dependent expression of a transcription factor, Ad4BP, regulating steroidogenic P-450 genes in the gonads during prenatal and postnatal rat development. Development 120, 2787–2797. Hatano, O., Takakusu, A., Nomura, M., Morohashi, K., 1996. Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF-1. Genes to Cells 1, 663–671. Hirokawa, N., Ishikawa, H., 1974. Electron microscopic observations on postnatal development of the X zone in mouse adrenal cortex. Z Anat Entwicklungsgesch 144, 85–100. Holmes, P.V., Dickson, A.D., 1971. X-zone degeneration in the adrenal glands of adult and immature female mice. Journal of Anatomy 108, 159–168. Howard-Miller, E., 1927. A transitory zone in the adrenal cortex which shows age and sex relationships. American Journal of Anatomy 40, 251–293. Ingraham, H.A., Lala, D.S., Ikeda, Y., Luo, X., Shen, W.H., Nachtigal, M.W., Abbud, R., Nilson, J.H., Parker, K.L., 1994. The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes & Development 8, 2302–2312. Katoh-Fukui, Y., Owaki, A., Toyama, Y., Kusaka, M., Shinohara, Y., Maekawa, M., Toshimori, K., Morohashi, K., 2005. Mouse polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression. Blood 106, 1612–1620. Keegan, C.E., Hammer, G.D., 2002. Recent insights into organogenesis of the adrenal cortex. Trends in Endocrinology and Metabolism 13, 200–208. Lanman, J.T., 1953. The fetal zone of the adrenal gland: its developmental course, comparative anatomy, and possible physiologic functions. Medicine (Baltimore) 32, 389–430. Luo, X., Ikeda, Y., Parker, K.L., 1994. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77, 481–490. Masui, K., Tamura, Y., 1926. The effect of gonadectomy on the structure of the suprarenal gland of mice, with reference to the functional relation between this gland and the sex gland of the female. Jounal of the College of Agriculture, Imperialial Univesity of Tokyo 7, 353–376. Morohashi, K., 1997. The ontogenesis of the steroidogenic tissues. Genes to Cells 2, 95–106.
K.-i. Morohashi, M. Zubair / Molecular and Cellular Endocrinology 336 (2011) 193–197 Morohashi, K., Tsuboi-Asai, H., Matsushita, S., Suda, M., Nakashima, M., Sasano, H., Hataba, Y., Li, C.L., Fukata, J., Irie, J., Watanabe, T., Nagura, H., Li, E., 1999. Structural and functional abnormalities in the spleen of an mFtz-F1 gene-disrupted mouse. Blood 93, 1586–1594. Mouw, A.R., Rice, D.A., Meade, J.C., Chua, S.C., White, P.C., Schimmer, B.P., Parker, K.L., 1989. Structural and functional analysis of the promoter region of the gene encoding mouse steroid 11 beta-hydroxylase. The Journal of Biological Chemistry 264, 1305–1309. Nomura, M., Bartsch, S., Nawata, H., Omura, T., Morohashi, K., 1995. An E box element is required for the expression of the ad4 bp gene, a mammalian homologue of ftz-f1 gene, which is essential for adrenal and gonadal development. The Journal of Biological Chemistry 270, 7453–7461. Nomura, M., Nawata, H., Morohashi, K., 1996. Autoregulatory loop in the regulation of the mammalian ftz-f1 gene. The Journal of Biological Chemistry 271, 8243–8249. Rice, D.A., Aitken, L.D., Vandenbark, G.R., Mouw, A.R., Franklin, A., Schimmer, B.P., Parker, K.L., 1989. A cAMP-responsive element regulates expression of the mouse steroid 11 beta-hydroxylase gene. The Journal of Biological Chemistry, 14011–14015. Rice, D.A., Kronenberg, M.S., Mouw, A.R., Aitken, L.D., Franklin, A., Schimmer, B.P., Parker, K.L., 1990a. Multiple regulatory elements determine adrenocortical expression of steroid 21-hydroxylase. The Journal of Biological Chemistry 265, 8052–8058. Rice, D.A., Kirkman, M.S., Aitken, L.D., Mouw, A.R., Schimmer, B.P., Parker, K.L., 1990b. Analysis of the promoter region of the gene encoding mouse cholesterol sidechain cleavage enzyme. The Journal of Biological Chemistry 265, 11713–11720. Sadovsky, Y., Crawford, P.A., Woodson, K.G., Polish, J.A., Clements, M.A., Tourtellotte, L.M., Simburger, K., Milbrandt, J., 1995. Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 sidechain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proceedings of National Academy of Sciences of the United States of America 92, 10939–10943.
197
Shima, Y., Zubair, M., Ishihara, S., Shinohara, Y., Oka, S., Kimura, S., Okamoto, S., Minokoshi, Y., Suita, S., Morohashi, K., 2005. Ventromedial hypothalamic nucleus-specific enhancer of Ad4BP/SF-1 gene. Molecular Endocrinology 19, 2812–2823. Shima, Y., Zubair, M., Komatsu, T., Oka, S., Yokoyama, C., Tachibana, T., Hjalt, T.A., Drouin, J., Morohashi, K., 2008. Pituitary homeobox 2 regulates adrenal4 binding protein/steroidogenic factor-1 gene transcription in the pituitary gonadotrope through interaction with the intronic enhancer. Molecular Endocrinology 22, 1633–1646. Shinoda, K., Lei, H., Yoshii, H., Nomura, M., Nagano, M., Shiba, H., Sasaki, H., Osawa, Y., Ninomiya, Y., Niwa, O., et al., 1995. Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Developmental Dynamics 204, 22–29. Soriano, P., 1999. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nature Genetics 21, 70–71. Uotila, U., 1940. The early embryological development of the fetal and permanent adrenal cortex in man. Anatomical Research 76, 183–203. Yoshioka, H., Ishimaru, Y., Sugiyama, N., Tsunekawa, N., Noce, T., Kasahara, M., Morohashi, K., 2005. Mesonephric FGF signaling is associated with the development of sexually indifferent gonadal primordium in chick embryos. Developmental Biology 280, 150–161. Zubair, M., Ishihara, S., Oka, S., Okumura, K., Morohashi, K., 2006. Two-step regulation of Ad4BP/SF-1 gene transcription during fetal adrenal development: initiation by a Hox–Pbx1–Prep1 complex and maintenance via autoregulation by Ad4BP/SF-1. Molecular and Cellular Biology 26, 4111– 4121. Zubair, M., Parker, K.L., Morohashi, K., 2008. Developmental links between the fetal and adult zones of the adrenal cortex revealed by lineage tracing. Molecular and Cellular Biology 28, 7030–7040. Zubair, M., Oka, S., Parker, K.L., Morohashi, K., 2009. Transgenic expression of Ad4BP/SF-1 in fetal adrenal progenitor cells leads to ectopic adrenal formation. Molecular Endocrinology 23, 1657–1667.
Contents lists available at ScienceDirect
Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce
Review
The fetal and adult adrenal cortex Ken-ichirou Morohashi a,∗ , Mohamad Zubair b a b
Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan Department of Internal Medicine, Division of Metabolism Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109-2200, USA
a r t i c l e
i n f o
Article history: Received 2 October 2010 Received in revised form 23 November 2010 Accepted 23 November 2010 Keywords: Ad4BP/SF-1 Adrenal cortex Steroid hormone Enhancer Fetal adrenal
a b s t r a c t The orphan nuclear receptor AD4BP/SF-1 (adrenal-4-binding protein/steroidogenic factor-1 (NR5A1)) is essential for the proper development and function of reproductive and steroidogenic tissues. Although the expression of Ad4BP/Sf-1 is specific for those tissues, the mechanisms underlying this tissue-specific expression remain unknown. Our transgenic studies have identified the tissue-specific enhancers for the fetal adrenal cortex, ventromedial hypothalamus, and pituitary in Ad4BP/Sf-1 gene. The adrenal cortex forms morphologically distinct compartments, the inner (fetal) and outer (definitive or adult) zones. Despite considerable effort, the mechanisms that mediate the differential development of the fetal and adult adrenal cortex remain incompletely understood. It remained controversial whether a true fetal type adrenal cortex is present in mice, and this argument was complicated by the postnatal development of the so-called X-zone. Using transgenic mice with lacZ driven by the fetal adrenal enhancer (FAdE), we clearly identified a fetal adrenal cortex in mice, and the X-zone is the fetal adrenal cells accumulated at the juxtamedullary region after birth. We combined the FAdE with the Cre/loxP system to trace cell lineages in which the FAdE was active at some stage in development. These lineage tracing studies establish definitively that the adult cortex derives from precursor cells in the fetal cortex in which the FAdE was activated before the organization into two distinct zones. The potential of these fetal adrenocortical cells to enter the pathway that eventuate in cells of the adult cortex disappeared by E14.5. Thus, these studies demonstrate a direct link between the fetal and adult cortex involving a transition that must occur before a specific stage of development. © 2010 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Identification of fetal adrenal enhancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Correlation of fetal zone and X-zone in the developing mouse adrenal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lineage tracing of the fetal adrenal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Temporal window in which FAdE-active cells can contribute to the adult adrenal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The orphan nuclear receptor, AD4BP/SF-1 (adrenal 4 binding protein/steroidogenic factor-1), has been extensively studied in relation to its key function in steroidogenic gene regulation. Early
Abbreviations: Ad4BP/SF-1, adrernal 4 binding protein/steroidogenic factor-1; FAdE, fetal adrenal enhancer; EGFP, enhanced green fluorescence protein; AGP, adreno-gonad primordium. ∗ Corresponding author. Tel.: +81 92 642 6180; fax: +81 92 642 6181. E-mail address: [email protected] (K.-i. Morohashi). 0303-7207/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2010.11.026
193 194 195 195 196 196 196
studies focused on the transcriptional activity in certain cell types located in the gonads (testis and ovary) and adrenocortical cells. However, gene disruption studies have definitively revealed that Ad4BP/Sf-1 not only functions as a steroidogenic gene regulator, but also functions as an important trophic factor required for establishing and/or maintaining steroidogenic tissues (Luo et al., 1994). Furthermore, expression of the Ad4BP/Sf-1 gene has been detected in the ventromedial hypothalamus (VMH) and the pituitary gonadotrophs (Ingraham et al., 1994; Shinoda et al., 1995; Sadovsky et al., 1995). In addition to its function as a trophic factor in steroidogenesis, Ad4BP/Sf-1 is also essential for the establishment of the VMH and pituitary gonadotrophs. Ad4BP/Sf-1 has also been
194
K.-i. Morohashi, M. Zubair / Molecular and Cellular Endocrinology 336 (2011) 193–197
identified in the spleen (Morohashi et al., 1999; Katoh-Fukui et al., 2005). The phenotype of Ad4BP/Sf-1 KO mice has clearly demonstrated that mechanisms which enable tissue-specific gene expression are critical for the development of those tissues. This regulatory mechanism for Ad4BP/Sf-1 gene expression was studied with cultured cells using the 5 upstream region of the gene. However, based on the results of our own studies of the of the Ad4BP/Sf-1 promoter (Nomura et al., 1995, 1996), we predicted that tissue-specific expression of the gene is regulated not only by the 5 upstream region but tissue-specific enhancers which had been unidentified yet. Therefore, we started to identify the tissue-specific enhancers of the Ad4BP/Sf-1 gene using transgenic (Tg) mouse assays. Partially digested mouse genomic DNA fragments were inserted into a modified cosmid vector containing the 5 upstream region of the gene and EGFP or bacterial lacZ reporter gene. Cosmid clones carrying DNA fragments of the Ad4BP/Sf-1 gene locus were directly subjected to Tg assays. From these, a clone was obtained, which had the potential to induce reporter gene expression in the fetal adrenal cortex (Zubair et al., 2006), ventral diencephalon (the future VMH) (Shima et al., 2005), and Rathke’s pouch (pituitary anlage) (Shima et al., 2008). Thus, in consequence, we localized the enhancer sequences for the fetal adrenal cortex in the fourth intron and for the VMH and pituitary enhancers in the sixth intron. Interestingly, these sequences are conserved among animal species (Fig. 1). 2. Identification of fetal adrenal enhancer Using Tg mouse lines, we characterized the activity of the fetal adrenal-specific enhancer (FAdE). LacZ reporter expression was observed at the medial side of the urogenital ridges at E10.5. The
Fig. 1. Localization of enhancers for fetal adrenal cortex, VMH, and pituitary gonadotroph. The tissue-specific enhancers of Ad4BP/SF-1 gene were localized within the fourth and sixth introns by transgenic mouse assays. All enhancer regions contained multiple sequences conserved among animal species. They are the consensus binding sequences for Ad4BP/SF-1 and Hox/Pbx/Prep in the fetal adrenal enhancer, a consensus binding sequence for Homeo box protein for the VMH enhancer, and a consensus binding sequence for Pitx2 in the pituitary enhancer. The activities of all these sites are lost when mutations are introduced.
results of our previous studies demonstrated that the gonad and adrenal cortex form a single cell group, the adreno-gonad primordium (AGP) (Morohashi, 1997). Cross-sections of rat fetuses (Hatano et al., 1994, 1996) and chick embryos (Yoshioka et al., 2005) revealed that AGP localizes from the coelomic epithelium (ventral domain) in the area proximal to the dorsal aorta (dorsal domain) as a single and AD4BP/SF-1 positive cell population (Fig. 2). When the Tg mouse fetuses stained with lacZ were cross-sectioned, the
Fig. 2. Schematic presentation of early adrenal and gonadal development. (A) AD4BP/SF-1 is the marker protein of the adrenal cortex and gonad from the early stage of tissue development. In our previous studies, we found that the adrenal primordium (AP) and gonad primordium (GP) formed a single AD4BP/SF-1 positive cell population. Thus, we termed the AD4BP/SF-1 positive cells the adreno-gonad primordium (AGP). While these cells were all immunoreactive for AD4BP/SF-1, it was not known if these cells used the same enhancer. However, our transgenic studies demonstrated that FAdE was activated in the dorsal (dark grey with an arrow labeled with AP) but not in the ventral region (light grey with an arrow labeled with GP) at E11.5. This observation indicated that the AP and GP were differentiated at E11.5 even though they formed a single cell population that was AD4BP/SF-1 positive. Thereafter, at E12.5 they were morphologically divided into two subpopulations, AP and GP. (B) Adrenal cortical and gonadal somatic cells (Sertoli and Leydig cells) are derived from the same progenitor cells (AGP). They give rise to two precursor cells for the adrenal cortex (AP) and gonad, respectively. FAdE is activated in the AP cells, but not in the gonadal precursor cells. Soon after, some cells in the AP change the usage of the enhancer from FAdE to an as of yet unidentified adult adrenal enhancer.
K.-i. Morohashi, M. Zubair / Molecular and Cellular Endocrinology 336 (2011) 193–197
195
Fig. 3. Transition of the adrenal cortex from fetal to adult. The transition processes in a mouse and human are illustrated. During the fetal stage, the adrenal cortex consists of an outer definitive adult zone (light grey) and an inner fetal zone (dark grey). Thereafter, the fetal zone becomes thinner while the adult zone becomes thicker during the fetal age in the mouse and after birth in humans. Interestingly, the fetal cells sporadically distribute in the medulla afterbirth (neonatal stage) in the mouse, and thereafter form the inner cell layer again. This newly formed cell layer disappears soon at the pubertal stage in males but persists so that it is present until first pregnancy in females.
lacZ signal was clearly localized within the area corresponding to the dorsal domain of the AGP (Zubair et al., 2006). This lacZ expression strongly suggested that the FAdE was used in the dorsal cells while the other unknown enhancer was activated within the ventral cells. Subsequently, AGP divided into two separate primordia; the adrenal primordium (AP) and the gonadal primordium (GP). LacZ activity became unexpectedly weak at E17.5. A crosssectional analysis revealed a small population of lacZ-positive cortical cells proximal to the medulla; all other cells remained inactive and this staining pattern was maintained until the neonatal period. However, by postnatal day 12 (P12), lacZ signals were detected sporadically throughout the medulla and thereafter accumulated again around the medulla. By P35, lacZ-expressing cells were mostly absent from the male tissue; but, although decreased in quantity, lacZ-positive cells persisted in females at the innermost cortical layer until P53. These cells completely regressed during the first pregnancy (Fig. 3). This expression profile indicates that the enhancer was unable to drive transgenetic expression in the adult adrenal cortex and suggests that another unidentified adult adrenal enhancer would drive gene expression in the adult. Therefore, there appear to be different systems for gene regulation within the fetal and adult adrenal cortex. 3. Correlation of fetal zone and X-zone in the developing mouse adrenal cortex
birth (Masui and Tamura, 1926; Howard-Miller, 1927). This particular layer disappears during puberty in male mice (Howard-Miller, 1927), but persists in female mice until the first pregnancy (Holmes and Dickson, 1971). Our Tg study with FAdE indicated that the fetal adrenal cortex was present in males until puberty and remained present in females until after sexual maturation. Moreover, lacZ expression in females completely disappeared after the first pregnancy (Fig. 3). This expression pattern was remarkably similar to the kinetics of X-zone regression, strongly implying that the lacZ expressing cells (fetal adrenal cortex) comprise the X-zone. However, the Xzone is believed to emerge after birth. This discrepancy may arise from the unique distribution of lacZ-positive fetal adrenal cells during the neonatal period. Shortly after birth, lacZ positive cells are distributed sporadically in the medulla, and thereafter, they accumulate in the juxtamedullary region, where the development of the develop X-zone is believed to occur (Hirokawa and Ishikawa, 1974). Previous studies examining the X-zone have utilized structural and histological observations rather than studying marker gene expression and this has made it difficult to establish the origins of the X-zone. Overall, our results demonstrate that the fetal adrenal zone is present in the mouse fetus and is maintained after birth as X-zone cells. Furthermore, we have also observed that the development of the mouse adrenal gland appears to be similar to that of other mammals. 4. Lineage tracing of the fetal adrenal cortex
The fetal adrenal cortices of many mammalian species consists of two distinct cell groups; small and tightly packed outer cells which form the adult zone, and the larger and irregularly aligned inner cells forming the fetal zone (Keegan and Hammer, 2002). During gestation, the fetal zone is enlarged and synthesizes steroids, while the adult zone remains undifferentiated. Following birth, the fetal zone regresses while the adult zone increases in size. Although both the rat and mouse fetal adrenal cortices develop the two distinct layers as with other mammalian species, their adrenal glands lack a ‘true’ fetal zone (Lanman, 1953). Rather, the fetal zone degeneration and growth of the adult zone starts in the late fetal stage of these rodents. Additionally, the mouse adrenal cortex develops a unique islet of eosinophilic cells, the so-called X-zone, after
The fetal adrenal cortex of many mammalian species consists of adult/definitive and fetal zones of which origins remain poorly understood. Morphological studies have led to the proposal of three different models to explain the origins of the adrenal cortex. One model proposes that the adult zone may be derived from the coelomic epithelia following the migration of the cells that form the fetal zone (Uotila, 1940). An alternative model is that the fetal and adult zones may be derived simultaneously from discrete populations of coelomic epithelial cells (Crowder, 1957). Both these models postulate that the cells comprising the fetal and adult zones are pre-determined in their cell fates when they develop from the coelomic epithelia. In contrast, the third model postulates that both
196
K.-i. Morohashi, M. Zubair / Molecular and Cellular Endocrinology 336 (2011) 193–197
zones differentiate from a single progenitor population that subsequently differentiates into distinct fetal and adult zones. To address which model is accurate, fetal adrenal cells were traced using Tg mice in which Cre recombinase was expressed by FAdE (Zubair et al., 2008). Tg mice were mated with ROSA26R reporter mice (Soriano, 1999) to trace the lacZ-positive fetal adrenal cells. LacZ expression was examined in the Cre/ROSA Tg male mice until 2 months after birth. As mentioned above, lacZ staining persisted in the inner part of the adrenal cortex (corresponding to the X zone) of the Tg mice, in which lacZ was driven by FAdE (normal Tg mice), but disappeared in the adult adrenal. By contrast, lacZ was clearly detectable not only in the fetal adrenal cortex but throughout the adult cortex of Cre/ROSA Tg mice, clearly indicating that the adult adrenal cortex is derived from fetal adrenal cells.
5. Temporal window in which FAdE-active cells can contribute to the adult adrenal cortex The next question that arose to us was whether or not fetal adrenal cells of all stages have the ability to differentiate into the adult adrenal cortex. To address this question, we generated transgenic mice with Cre-ERT2 expression under the control of FAdE (Zubair et al., 2008). Moreover, the Cre-ERT2 fusion protein is activated only in the presence of tamoxifen. Thus, Cre-mediated recombination should occur only when Tg mice are treated with tamoxifen. Tamoxifen was administered at E11.5, E14.5, or P6, and the mice were examined two months after birth. Most adult cortical cells of the mice treated at E11.5 expressed lacZ. However, if tamoxifen treatment was delayed until E14.5 or postnatal day 6, the cells that retained lacZ expression were not present in the adult adrenal cortex. These results demonstrate that fetal adrenal cells are capable of differentiating into adult adrenal cells and the ability disappeared by E14.5. The cell lineage studies above strongly support the third model, as they show that the adult zone is derived from the early stages of the fetal adrenal cortical zone. Interestingly, the capacity of these precursors to differentiate into the adult zone largely disappears by E14.5. Indeed, the adrenal primordia of Ad4BP–lacZ–FAdE Tg mice at E11.5 to E12.5 contain variable amounts of cells that weakly express lacZ, which presumably are in the process of extinguishing the FAdE activation. By E14.5, these cells preferentially localize in a thin layer at the surface of the cortex possibly to form the adult cortical zone. Importantly, we propose that the transition simultaneously involves a change in enhancer usage in the Ad4BP/Sf-1 locus from the FAdE to an adult adrenal enhancer, which remains to be identified. Further research is required to determine what induces such cell fate change from the fetal to adult cells; or what induces change of enhancer usage from FAdE to an unidentified adult adrenal enhancer remains. These studies will help us to figure out the whole process of adrenal development. In the series of studies, we demonstrated that Ad4BP/SF-1 gene is regulated by multiple tissue-specific enhancers. Since these enhancers are capable of activating any gene expression in tissuespecific manners, we generated Tg mouse lines in which GFP or Cre is expressed under the control of FAdE. Investigation of the Tg mouse lines clarified two issues. One of them is that X-zone cells of postnatal adrenal glands are the descendents of the fetal adrenal cortex. The other of them is that adult adrenal cortex is derived from fetal adrenal cortex, and the fetal adrenal cortex before E14.5 retains its ability to differentiate into adult adrenal cortex. In addition to these findings, we recently identified fetal Leydig enhancer, and established Tg mouse lines as we did with FAdE. As I mentioned previously, the fetal adrenal cortex and testicular Leydig cells have been discussed to be derived from same primordial cells. In order
to figure out the whole view of the steroidogenic cell development, the mouse lines generated using FAdE and fetal Leydig enhancer would be powerful tools.
Acknowledgments As mentioned above, the tissue-specific enhancers can potentially induce expression of any gene in a tissue-specific manner. Therefore, the enhancers are powerful tools to study and understand the mechanisms underlying tissue development. We started our collaborative studies with Keith by using the FAdE, and our studies were subsequently published in 2008 (Zubair et al., 2008) and 2009 (Zubair et al., 2009). The time we spent with Keith in preparing the manuscripts is a precious personal memory. My career (Ken Morohashi) as a scientist commenced with reading his papers describing steroidogenic gene regulation. I found these to be an excellent and interesting read (Handler et al., 1988; Mouw et al., 1989; Rice et al., 1989, 1990a,b; Bogerd et al., 1990). Since the factor he identified was identical with what I identified, I was able to work with him in the same field for the last 20 years. We attended some of the same meetings, such as series of Adrenal Conference and Molecular Steroidogenesis. It was my pleasure to hear of his various successes and hopefully for him to hear of mine. I believe that his presence has helped me improve the quality of my science, and also created an exciting and productive life as a scientist. I greatly appreciate not only his outstanding contribution to the medical and biological fields but also his fairness, friendship, and warm hospitality.
References Bogerd, A.M., Franklin, A., Rice, D.A., Schimmer, B.P., Parker, K.L., 1990. Identification and characterization of two upstream elements that regulate adrenocortical expression of steroid 11 beta-hydroxylase. Molecular Endocrinology 4, 845–850. Crowder, R., 1957. The development of the adrenal gland in man, with special reference to origin and ultimate location of cell types and evidence in favor of the “cell migration” theory. Contemporary Embryology 251, 195–209. Handler, J.D., Schimmer, B.P., Flynn, T.R., Szyf, M., Seidman, J.G., Parker, K.L., 1988. An enhancer element and a functional cyclic AMP-dependent protein kinase are required for expression of adrenocortical 21-hydroxylase. The Journal of Biological Chemistry 263, 13068–13073. Hatano, O., Takayama, K., Imai, T., Waterman, M.R., Takakusu, A., Omura, T., Morohashi, K., 1994. Sex-dependent expression of a transcription factor, Ad4BP, regulating steroidogenic P-450 genes in the gonads during prenatal and postnatal rat development. Development 120, 2787–2797. Hatano, O., Takakusu, A., Nomura, M., Morohashi, K., 1996. Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF-1. Genes to Cells 1, 663–671. Hirokawa, N., Ishikawa, H., 1974. Electron microscopic observations on postnatal development of the X zone in mouse adrenal cortex. Z Anat Entwicklungsgesch 144, 85–100. Holmes, P.V., Dickson, A.D., 1971. X-zone degeneration in the adrenal glands of adult and immature female mice. Journal of Anatomy 108, 159–168. Howard-Miller, E., 1927. A transitory zone in the adrenal cortex which shows age and sex relationships. American Journal of Anatomy 40, 251–293. Ingraham, H.A., Lala, D.S., Ikeda, Y., Luo, X., Shen, W.H., Nachtigal, M.W., Abbud, R., Nilson, J.H., Parker, K.L., 1994. The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes & Development 8, 2302–2312. Katoh-Fukui, Y., Owaki, A., Toyama, Y., Kusaka, M., Shinohara, Y., Maekawa, M., Toshimori, K., Morohashi, K., 2005. Mouse polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression. Blood 106, 1612–1620. Keegan, C.E., Hammer, G.D., 2002. Recent insights into organogenesis of the adrenal cortex. Trends in Endocrinology and Metabolism 13, 200–208. Lanman, J.T., 1953. The fetal zone of the adrenal gland: its developmental course, comparative anatomy, and possible physiologic functions. Medicine (Baltimore) 32, 389–430. Luo, X., Ikeda, Y., Parker, K.L., 1994. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77, 481–490. Masui, K., Tamura, Y., 1926. The effect of gonadectomy on the structure of the suprarenal gland of mice, with reference to the functional relation between this gland and the sex gland of the female. Jounal of the College of Agriculture, Imperialial Univesity of Tokyo 7, 353–376. Morohashi, K., 1997. The ontogenesis of the steroidogenic tissues. Genes to Cells 2, 95–106.
K.-i. Morohashi, M. Zubair / Molecular and Cellular Endocrinology 336 (2011) 193–197 Morohashi, K., Tsuboi-Asai, H., Matsushita, S., Suda, M., Nakashima, M., Sasano, H., Hataba, Y., Li, C.L., Fukata, J., Irie, J., Watanabe, T., Nagura, H., Li, E., 1999. Structural and functional abnormalities in the spleen of an mFtz-F1 gene-disrupted mouse. Blood 93, 1586–1594. Mouw, A.R., Rice, D.A., Meade, J.C., Chua, S.C., White, P.C., Schimmer, B.P., Parker, K.L., 1989. Structural and functional analysis of the promoter region of the gene encoding mouse steroid 11 beta-hydroxylase. The Journal of Biological Chemistry 264, 1305–1309. Nomura, M., Bartsch, S., Nawata, H., Omura, T., Morohashi, K., 1995. An E box element is required for the expression of the ad4 bp gene, a mammalian homologue of ftz-f1 gene, which is essential for adrenal and gonadal development. The Journal of Biological Chemistry 270, 7453–7461. Nomura, M., Nawata, H., Morohashi, K., 1996. Autoregulatory loop in the regulation of the mammalian ftz-f1 gene. The Journal of Biological Chemistry 271, 8243–8249. Rice, D.A., Aitken, L.D., Vandenbark, G.R., Mouw, A.R., Franklin, A., Schimmer, B.P., Parker, K.L., 1989. A cAMP-responsive element regulates expression of the mouse steroid 11 beta-hydroxylase gene. The Journal of Biological Chemistry, 14011–14015. Rice, D.A., Kronenberg, M.S., Mouw, A.R., Aitken, L.D., Franklin, A., Schimmer, B.P., Parker, K.L., 1990a. Multiple regulatory elements determine adrenocortical expression of steroid 21-hydroxylase. The Journal of Biological Chemistry 265, 8052–8058. Rice, D.A., Kirkman, M.S., Aitken, L.D., Mouw, A.R., Schimmer, B.P., Parker, K.L., 1990b. Analysis of the promoter region of the gene encoding mouse cholesterol sidechain cleavage enzyme. The Journal of Biological Chemistry 265, 11713–11720. Sadovsky, Y., Crawford, P.A., Woodson, K.G., Polish, J.A., Clements, M.A., Tourtellotte, L.M., Simburger, K., Milbrandt, J., 1995. Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 sidechain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proceedings of National Academy of Sciences of the United States of America 92, 10939–10943.
197
Shima, Y., Zubair, M., Ishihara, S., Shinohara, Y., Oka, S., Kimura, S., Okamoto, S., Minokoshi, Y., Suita, S., Morohashi, K., 2005. Ventromedial hypothalamic nucleus-specific enhancer of Ad4BP/SF-1 gene. Molecular Endocrinology 19, 2812–2823. Shima, Y., Zubair, M., Komatsu, T., Oka, S., Yokoyama, C., Tachibana, T., Hjalt, T.A., Drouin, J., Morohashi, K., 2008. Pituitary homeobox 2 regulates adrenal4 binding protein/steroidogenic factor-1 gene transcription in the pituitary gonadotrope through interaction with the intronic enhancer. Molecular Endocrinology 22, 1633–1646. Shinoda, K., Lei, H., Yoshii, H., Nomura, M., Nagano, M., Shiba, H., Sasaki, H., Osawa, Y., Ninomiya, Y., Niwa, O., et al., 1995. Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Developmental Dynamics 204, 22–29. Soriano, P., 1999. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nature Genetics 21, 70–71. Uotila, U., 1940. The early embryological development of the fetal and permanent adrenal cortex in man. Anatomical Research 76, 183–203. Yoshioka, H., Ishimaru, Y., Sugiyama, N., Tsunekawa, N., Noce, T., Kasahara, M., Morohashi, K., 2005. Mesonephric FGF signaling is associated with the development of sexually indifferent gonadal primordium in chick embryos. Developmental Biology 280, 150–161. Zubair, M., Ishihara, S., Oka, S., Okumura, K., Morohashi, K., 2006. Two-step regulation of Ad4BP/SF-1 gene transcription during fetal adrenal development: initiation by a Hox–Pbx1–Prep1 complex and maintenance via autoregulation by Ad4BP/SF-1. Molecular and Cellular Biology 26, 4111– 4121. Zubair, M., Parker, K.L., Morohashi, K., 2008. Developmental links between the fetal and adult zones of the adrenal cortex revealed by lineage tracing. Molecular and Cellular Biology 28, 7030–7040. Zubair, M., Oka, S., Parker, K.L., Morohashi, K., 2009. Transgenic expression of Ad4BP/SF-1 in fetal adrenal progenitor cells leads to ectopic adrenal formation. Molecular Endocrinology 23, 1657–1667.