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David L. Page - One of the best experts on this subject based on the ideXlab platform.
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licensing of primordial Germ Cells for gametogenesis depends on genital ridge signaling
PLOS Genetics, 2015Co-Authors: Peter K. Nicholls, David L. Page, Y. Shirleen Q. Soh, Joseph R. Daniele, Jan Philipp Junker, Alexander Van OudenaardenAbstract:In mouse embryos at mid-gestation, primordial Germ Cells (PGCs) undergo licensing to become gametogenesis-competent Cells (GCCs), gaining the capacity for meiotic initiation and sexual differentiation. GCCs then initiate either oogenesis or spermatogenesis in response to gonadal cues. Germ cell licensing has been considered to be a cell-autonomous and gonad-independent event, based on observations that some PGCs, having migrated not to the gonad but to the adrenal gland, nonetheless enter meiosis in a time frame parallel to ovarian Germ Cells -- and do so regardless of the sex of the embryo. Here we test the hypothesis that Germ cell licensing is cell-autonomous by examining the fate of PGCs in Gata4 conditional mutant (Gata4 cKO) mouse embryos. Gata4, which is expressed only in somatic Cells, is known to be required for genital ridge initiation. PGCs in Gata4 cKO mutants migrated to the area where the genital ridge, the precursor of the gonad, would ordinarily be formed. However, these Germ Cells did not undergo licensing and instead retained characteristics of PGCs. Our results indicate that licensing is not purely cell-autonomous but is induced by the somatic genital ridge.
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sex specific chromatin states in mammalian fetal Germ Cells
Epigenetics & Chromatin, 2013Co-Authors: Bluma J Lesch, David L. PageAbstract:Background Male and female mammalian Germ Cells follow identical developmental trajectories for the first half of embryogenesis, during which time they also maintain a pluripotentlike state. Beginning around day 13.5 of embryogenesis (E13.5), male and female Germ Cells initiate dramatically different developmental programs: female Germ Cells enter meiotic prophase, while male Germ Cells enter a G0-like cell cycle arrest until after birth [1]. At this time, both male and female Germ Cells also lose the ability to establish pluripotent cell lines in culture [2]. As late as E12.5, male and female Germ Cells are morphologically identical, and few transcriptional differences can be detected [1,3]. To evaluate the coordination of sex-specific transcriptional states during this important interval in Germ cell differentiation, we examined placement of the activating histone modification H3K4me3 and the repressive histone modification H3K27me3 in XX and XY murine Germ Cells before and during the initiation of sex differentiation.
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sexual differentiation of Germ Cells in xx mouse gonads occurs in an anterior to posterior wave
Developmental Biology, 2003Co-Authors: Douglas B Menke, Jana Koubova, David L. PageAbstract:Differentiation of mouse embryonic Germ Cells as male or female is dependent on the somatic environment of the gonad rather than the sex chromosome constitution of the Germ cell. However, little is known about the initiation of Germ cell sexual differentiation. Here, we traced the initiation of Germ cell sexual differentiation in XX gonads using the Stra8 gene, which we demonstrate is an early molecular marker of female Germ cell development. Stra8 is upregulated in embryonic Germ Cells of XX gonads prior to meiotic entry and is not expressed in male embryonic Germ Cells. A developmental time course of Stra8 expression in Germ Cells of XX gonads has revealed an anterior-to-posterior wave of differentiation that lasts approximately 4 days, from embryonic days 12.5 to 16.5. Consistent with these results, we find that embryonic ovarian Germ Cells upregulate the meiotic gene Dmc1 and downregulate the Oct4 transcription factor in an anterior-to-posterior wave. In complementary experiments, we find that embryonic XX gonads upregulate certain gene markers of somatic female differentiation in an anterior-to-posterior pattern, while others display a center-to-pole pattern of regulation. Thus, sexual differentiation and meiotic entry of Germ Cells in embryonic XX gonads progress in an anterior-to-posterior pattern that may reflect local environmental cues that are present in the embryonic XX gonad.
Martin Petkovich - One of the best experts on this subject based on the ideXlab platform.
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cyp26b1 expression in murine sertoli Cells is required to maintain male Germ Cells in an undifferentiated state during embryogenesis
PLOS ONE, 2009Co-Authors: Glenn Maclean, Don Cameron, Margaret Clagettdame, Martin PetkovichAbstract:In mammals, Germ Cells within the developing gonad follow a sexually dimorphic pathway. Germ Cells in the murine ovary enter meiotic prophase during embryogenesis, whereas Germ Cells in the embryonic testis arrest in G0 of mitotic cell cycle and do not enter meiosis until after birth. In mice, retinoic acid (RA) signaling has been implicated in controlling entry into meiosis in Germ Cells, as meiosis in male embryonic Germ Cells is blocked by the activity of a RA-catabolizing enzyme, CYP26B1. However, the mechanisms regulating mitotic arrest in male Germ Cells are not well understood. Cyp26b1 expression in the testes begins in somatic Cells at embryonic day (E) 11.5, prior to mitotic arrest, and persists throughout fetal development. Here, we show that Sertoli cell-specific loss of CYP26B1 activity between E15.5 and E16.5, several days after Germ cell sex determination, causes male Germ Cells to exit from G0, re-enter the mitotic cell cycle and initiate meiotic prophase. These results suggest that male Germ Cells retain the developmental potential to differentiate in meiosis until at least at E15.5. CYP26B1 in Sertoli Cells acts as a masculinizing factor to arrest male Germ Cells in the G0 phase of the cell cycle and prevents them from entering meiosis, and thus is essential for the maintenance of the undifferentiated state of male Germ Cells during embryonic development.
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apoptotic extinction of Germ Cells in testes of cyp26b1 knockout mice
Endocrinology, 2007Co-Authors: Glenn Maclean, Pierre Chambon, Hui Li, Daniel Metzger, Martin PetkovichAbstract:Cyp26b1 encodes a retinoic acid (RA) metabolizing cytochrome P450 enzyme that is expressed in embryonic tissues undergoing morphogenesis, including the testes. We have generated transgenic mice lacking Cyp26b1 and have observed increased RA levels in embryonic testes. Cyp26b1−/− Germ Cells prematurely enter meiosis at embryonic d 13.5 and appear to arrest at pachytene stage. Furthermore, after embryonic d 13.5, a rapid increase in apoptosis is observed in male Germ Cells derived from Cyp26b1−/− embryos; Germ Cells are essentially absent in mutant male neonates. In contrast, testicular somatic Cells appear to develop normally in the absence of Cyp26b1. Moreover, ovarian Germ and somatic Cells appear unaffected by the lack of CYP26B1. We also show that the synthetic retinoid Am580, which is resistant to CYP26 metabolism, induces meiosis of male Germ Cells in cultured gonads, suggesting that abnormal development of Germ Cells in the Cyp26b1−/− testes results from excess RA rather than the absence of CYP26B1-...
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Apoptotic extinction of Germ Cells in testes of Cyp26b1 knockout mice.
Endocrinology, 2007Co-Authors: Glenn Maclean, Pierre Chambon, Daniel Metzger, Martin PetkovichAbstract:Cyp26b1 encodes a retinoic acid (RA) metabolizing cytochrome P450 enzyme that is expressed in embryonic tissues undergoing morphogenesis, including the testes. We have generated transgenic mice lacking Cyp26b1 and have observed increased RA levels in embryonic testes. Cyp26b1(-/-) Germ Cells prematurely enter meiosis at embryonic d 13.5 and appear to arrest at pachytene stage. Furthermore, after embryonic d 13.5, a rapid increase in apoptosis is observed in male Germ Cells derived from Cyp26b1(-/-) embryos; Germ Cells are essentially absent in mutant male neonates. In contrast, testicular somatic Cells appear to develop normally in the absence of Cyp26b1. Moreover, ovarian Germ and somatic Cells appear unaffected by the lack of CYP26B1. We also show that the synthetic retinoid Am580, which is resistant to CYP26 metabolism, induces meiosis of male Germ Cells in cultured gonads, suggesting that abnormal development of Germ Cells in the Cyp26b1(-/-) testes results from excess RA rather than the absence of CYP26B1-generated metabolites of RA. These results provide evidence that CYP26B1 maintains low levels of RA in the developing testes that blocks entry into meiosis and acts as a survival factor to prevent apoptosis of male Germ Cells.
Minoru Tanaka - One of the best experts on this subject based on the ideXlab platform.
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Germ Cells in the teleost fish medaka have an inherent feminizing effect
PLOS Genetics, 2018Co-Authors: Toshiya Nishimura, Kazuki Yamada, Chika Fujimori, Mariko Kikuchi, Toshihiro Kawasaki, Kellee R Siegfried, Noriyoshi Sakai, Minoru TanakaAbstract:Germ Cells give rise to eggs or sperm. However, recent analyses in medaka (Oryzias latipes) showed that Germ Cells are also important for feminization of gonads, although this novel role of Germ Cells has not been characterized in detail. Here, we show that the feminizing effect is inherent to Germ Cells and is not affected by gametogenic stages or the sexual fate of Germ Cells. Three medaka mutants were generated to demonstrate this effect: figlα mutants, in which follicle formation is disrupted; meioC mutants, in which Germ Cells are unable to commit to gametogenesis and meiosis; and dazl mutants, in which Germ Cells do not develop into gonocytes. All these different stages of Germ Cells in XX mutants have an ability to feminize the gonads, resulting in the formation of gonads with ovarian structures. In addition to normal ovarian development, we also suggest that the increased number of gonocytes is sufficient for male to female sex reversal in XY medaka. These results may genetically demonstrate that the mechanism underlying the feminizing effect of Germ Cells is activated before the sexual fate decision of Germ Cells and meiosis, probably by the time of gonocyte formation in medaka. Author summary Germ Cells are the only Cells that can transfer genetic materials to the next generation via the sperm or egg. However, recent analyses in teleosts revealed another essential role of Germ Cells: feminizing the gonads. In our study, medaka mutants in which gametogenesis was blocked at specific stages provides the novel view that the feminizing effect of Germ Cells occurs in parallel with other reproductive elements, such as meiosis, the sexual fate decision of Germ Cells, and gametogenesis. Germ Cells in medaka may have a potential to feminize gonads at the moment they have developed.
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PGC-like Germ Cells in dazl mutants have the potential for feminization of gonads.
2018Co-Authors: Toshiya Nishimura, Kazuki Yamada, Chika Fujimori, Mariko Kikuchi, Toshihiro Kawasaki, Kellee R Siegfried, Noriyoshi Sakai, Minoru TanakaAbstract:(A–C) Morphology of type I Germ Cells observed by immunohistochemistry with OLVAS (green: Germ cell) and DAPI staining (gray). Arrowheads indicate nucleoli. dazl–/–Germ Cells at hatching stage (B) are morphologically similar to wild-type PGCs at stage 30 (C) in terms of the small cell-size and a nucleolus size compared to that of wild-type type I Germ Cells at hatching stage (A). (D–G) In situ hybridization of foxl3 and meioC in dazl–/–XX gonads at hatching stage. Arrowheads indicate foxl3 or meioC negative Germ Cells. A black dotted line indicates the region of gonads. (H) The number of Germ Cells in dazl–/–XX and XY gonads at hatching stage (0 dph) and 10 days post hatching (10 dph). * p
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hyperproliferation of mitotically active Germ Cells due to defective anti mullerian hormone signaling mediates sex reversal in medaka
Development, 2012Co-Authors: Shuhei Nakamura, Toshiya Nishimura, Ikuko Watakabe, Jeanyves Picard, Atsushi Toyoda, Yoshihito Taniguchi, Nathalie Di Clemente, Minoru TanakaAbstract:The function of AMH (Anti-Mullerian hormone), a phylogenetically ancient member of the TGFβ family of proteins, in lower vertebrates is largely unknown. Previously, we have shown that the gene encoding the type II anti-Mullerian hormone receptor, amhrII, is responsible for excessive Germ cell proliferation and male-to-female sex reversal in the medaka hotei mutant. In this study, functional analyses in cultured Cells and of other amhrII mutant alleles indicate that lack of AMH signaling causes the hotei phenotype. BrdU incorporation experiments identified the existence of both quiescent and mitotically active Germ Cells among the self-renewing, type I population of Germ Cells in the developing gonad. AMH signaling acts in supporting Cells to promote the proliferation of mitotically active Germ Cells but does not trigger quiescent Germ Cells to proliferate in the developing gonad. Furthermore, we show that the male-to-female sex reversal phenotype in hotei mutants is not a direct consequence of AMH signaling in supporting Cells, but is instead mediated by Germ Cells. Our data demonstrate that interfollicular AMH signaling regulates proliferation at a specific stage of Germ cell development, and that this regulation is crucial for the proper manifestation of gonadal sex directed by sex determination genes.
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Germ Cells are essential for sexual dimorphism in the medaka gonad
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Hiromi Kurokawa, Shuhei Nakamura, Yuko Katohfukui, Kohei Ohta, Takashi Aba, Ken Ichiro Morohashi, Minoru TanakaAbstract:To further elucidate the roles of Germ Cells in the sex differentiation of gonads, we have used the medaka, a teleost fish, to generate mutants that lack Germ Cells from the onset of gonadogenesis by the morpholino-mediated knockdown of cxcr4. The resulting Germ-cell-deficient medaka show female-to-male sex reversal of their secondary sex characteristics, accompanied by increased levels of androgen and reduced levels of estrogen. A failure to maintain granulosa Cells or estrogen-producing Cells also occurs at early stages of sex differentiation in the cxcr4 morphants, before the initiation of gonadal morphogenesis. In contrast, androgen-producing Cells are unaffected in Germ-cell-deficient medaka of either sex. In addition, a single tube-like gonad that expresses male-specific genes is formed in these mutants irrespective of the genetic sex. Significantly, each of these mutant phenotypes occurs in a somatic cell-autonomous manner, suggesting that gonadal somatic Cells are predisposed toward male development in the absence of Germ Cells. This highlights the importance of Germ Cells in the sexual dimorphism of the gonads.
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proliferation of Germ Cells during gonadal sex differentiation in medaka insights from Germ cell depleted mutant zenzai
Developmental Biology, 2007Co-Authors: Daisuke Saito, Shuhei Nakamura, Chikako Morinaga, Yumiko Aoki, Hiroshi Mitani, Makoto Furutaniseiki, Hisato Kondoh, Minoru TanakaAbstract:The proliferation of Germ Cells becomes sexually dimorphic during gonadal sex differentiation, although the underlying dynamics of this are not well understood in vertebrates. By tracing GFP-labeled Germ Cells in vivo and analyzing the Germ cell-depleted mutant, zenzai, we show that the proliferation and differentiation of Germ Cells are regulated in a sexually dimorphic manner in the teleost fish medaka. In the undifferentiated gonads, Germ Cells resume proliferation by slow intermittent division (type I), producing isolated daughter Cells. While Germ Cells in the male gonads continue this mode of proliferation, some Germ cell fractions in the female gonads initiate two to four rounds of continuous division (type II), forming cysts of four, eight, or sixteen Cells, which subsequently enter meiosis synchronously. Thus, female Germ Cells become differentiated much earlier than do male Germ Cells. In the zenzai mutant, a defect in slow intermittent division eventually leads to the depletion of Germ Cells in the adult gonads in both sexes, despite the fact that cyst-forming division is unaffected. This argues that slow intermittent division is essential for the maintenance of Germ Cells. The proliferation and differentiation of Germ Cells are thus important components of gonadal sex differentiation in vertebrates.
Petra Hajkova - One of the best experts on this subject based on the ideXlab platform.
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Epigenetic reprogramming of mouse Germ Cells toward totipotency.
Cold Spring Harbor symposia on quantitative biology, 2010Co-Authors: M.a. Surani, Petra HajkovaAbstract:Primordial Germ Cells (PGCs), the precursors of sperm and eggs, are the route to totipotency and require establishment of a unique epigenome in this lineage. The genetic program for PGC specification in the mouse also initiates epigenetic reprogramming that continues when PGCs migrate into the developing gonads. Among these later events is active and genome-wide DNA demethylation, which is linked to extensive chromatin remodeling. These extensive epigenetic changes erase most, if not all, of the existing epigenetic information, which resets the epigenome for totipotency. Recent evidence suggests that active DNA demethylation involves a base excision repair (BER) pathway. BER is mechanistically linked to DNA demethylation, but what triggers BER is currently under investigation. The methylated cytosine (5mC) could be modified by deamination or to 5hmC, which could induce BER. Detection of Tet1 expression specifically and coincidentally, at the time of BER in PGCs, suggests that conversion of 5mC to 5hmC might be involved, at least in part, during epigenetic reprogramming and DNA demethylation in Germ Cells.
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influence of sex chromosome constitution on the genomic imprinting of Germ Cells
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Gabriela Durcovahills, Petra Hajkova, Stephen R Sullivan, Sheila C Barton, Azim M Surani, A MclarenAbstract:Germ Cells in XY male mice establish site-specific methylation on imprinted genes during spermatogenesis, whereas Germ Cells in XX females establish their imprints in growing oocytes. We showed previously that in vitro, sex-specific methylation patterns of pluripotent stem cell lines derived from Germ Cells were influenced more by the sex chromosome constitution of the Cells themselves than by the gender of the embryo from which they had been derived. To see whether the same situation would prevail in vivo, we have now determined the methylation status of H19 expressed from the maternal allele, and the expression and methylation status of a paternally expressed gene Peg3, in Germ Cells from sex-reversed and control embryos. For these imprinted genes, we conclude that the female imprint is a response of the Germ Cells to undergoing oogenesis, rather than to their XX chromosome constitution. Similarly, both our XY and our sex-reversed XX male Germ Cells clearly showed a male rather than a female pattern of DNA methylation; here, however, the sex chromosome constitution had a significant effect, with XX male Germ Cells less methylated than the XY controls.
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blimp1 associates with prmt5 and directs histone arginine methylation in mouse Germ Cells
Nature Cell Biology, 2006Co-Authors: Katia Ancelin, Petra Hajkova, Ulrike C Lange, Robert Schneider, Andrew J Bannister, Tony Kouzarides, Azim M SuraniAbstract:Blimp1, a transcriptional repressor, has a crucial role in the specification of primordial Germ Cells (PGCs) in mice at embryonic day 7.5 (E7.5). This SET-PR domain protein can form complexes with various chromatin modifiers in a context-dependent manner. Here, we show that Blimp1 has a novel interaction with Prmt5, an arginine-specific histone methyltransferase, which mediates symmetrical dimethylation of arginine 3 on histone H2A and/or H4 tails (H2A/H4R3me2s). Prmt5 has been shown to associate with Tudor, a component of Germ plasm in Drosophila melanogaster. Blimp1-Prmt5 colocalization results in high levels of H2A/H4 R3 methylation in PGCs at E8.5. However, at E11.5, Blimp1-Prmt5 translocates from the nucleus to the cytoplasm, resulting in the loss of H2A/H4 R3 methylation at the time of extensive epigenetic reprogramming of Germ Cells. Subsequently, Dhx38, a putative target of the Blimp1-Prmt5 complex, is upregulated. Interestingly, expression of Dhx38 is also seen in pluripotent embryonic Germ Cells that are derived from PGCs when Blimp1 expression is lost. Our study demonstrates that Blimp1 is involved in a novel transcriptional regulatory complex in the mouse Germ-cell lineage.
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Epigenetic reprogramming in mouse primordial Germ Cells.
Mechanisms of development, 2002Co-Authors: Petra Hajkova, Wolf Reik, Sylvia Erhardt, Natasha Lane, Thomas Haaf, Osman El-maarri, Jörn Walter, M.a. SuraniAbstract:Genome-wide epigenetic reprogramming in mammalian Germ Cells, zygote and early embryos, plays a crucial role in regulating genome functions at critical stages of development. We show here that mouse primordial Germ Cells (PGCs) exhibit dynamic changes in epigenetic modifications between days 10.5 and 12.5 post coitum (dpc). First, contrary to previous suggestions, we show that PGCs do indeed acquire genome-wide de novo methylation during early development and migration into the genital ridge. However, following their entry into the genital ridge, there is rapid erasure of DNA methylation of regions within imprinted and non-imprinted loci. For most genes, the erasure commences simultaneously in PGCs in both male and female embryos, which is completed within 1 day of development. Based on the kinetics of this process, we suggest that this is an active demethylation process initiated upon the entry of PGCs into the gonadal anlagen. The timing of reprogramming in PGCs is crucial since it ensures that Germ Cells of both sexes acquire an equivalent epigenetic state prior to the differentiation of the definitive male and female Germ Cells in which new parental imprints are established subsequently. Some repetitive elements, however, show incomplete erasure, which may be essential for chromosome stability and for preventing activation of transposons to reduce the risk of Germline mutations. Aberrant epigenetic reprogramming in the Germ line would cause the inheritance of epimutations that may have consequences for human diseases as suggested by studies on mouse models.
Blanche Capel - One of the best experts on this subject based on the ideXlab platform.
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Germ Cells Are Not Required to Establish the Female Pathway in Mouse Fetal Gonads
PloS one, 2012Co-Authors: Danielle M. Maatouk, Lindsey Mork, Ashley Hinson, Akio Kobayashi, Andrew P. Mcmahon, Blanche CapelAbstract:The fetal gonad is composed of a mixture of somatic cell lineages and Germ Cells. The fate of the gonad, male or female, is determined by a population of somatic Cells that differentiate into Sertoli or granulosa Cells and direct testis or ovary development. It is well established that Germ Cells are not required for the establishment or maintenance of Sertoli Cells or testis cords in the male gonad. However, in the agametic ovary, follicles do not form suggesting that Germ Cells may influence granulosa cell development. Prior investigations of ovaries in which pre-meiotic Germ Cells were ablated during fetal life reported no histological changes during stages prior to birth. However, whether granulosa Cells underwent normal molecular differentiation was not investigated. In cases where Germ cell loss occurred secondary to other mutations, transdifferentiation of granulosa Cells towards a Sertoli cell fate was observed, raising questions about whether Germ Cells play an active role in establishing or maintaining the fate of granulosa Cells. We developed a group of molecular markers associated with ovarian development, and show here that the loss of pre-meiotic Germ Cells does not disrupt the somatic ovarian differentiation program during fetal life, or cause transdifferentiation as defined by expression of Sertoli markers. Since we do not find defects in the ovarian somatic program, the subsequent failure to form follicles at perinatal stages is likely attributable to the absence of Germ Cells rather than to defects in the somatic Cells.
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fgf9 promotes survival of Germ Cells in the fetal testis
Development, 2006Co-Authors: Leo Dinapoli, Jordan Batchvarov, Blanche CapelAbstract:In addition to its role in somatic cell development in the testis, our data have revealed a role for Fgf9 in XY Germ cell survival. In Fgf9-null mice, Germ Cells in the XY gonad decline in numbers after 11.5 days post coitum (dpc), while Germ cell numbers in XX gonads are unaffected. We present evidence that Germ Cells resident in the XY gonad become dependent on FGF9 signaling between 10.5 dpc and 11.5 dpc, and that FGF9 directly promotes XY gonocyte survival after 11.5 dpc, independently from Sertoli cell differentiation. Furthermore, XY Fgf9-null gonads undergo true male-to-female sex reversal as they initiate but fail to maintain the male pathway and subsequently express markers of ovarian differentiation (Fst and Bmp2). By 14.5 dpc, these gonads contain Germ Cells that enter meiosis synchronously with ovarian gonocytes. FGF9 is necessary for 11.5 dpc XY gonocyte survival and is the earliest reported factor with a sex-specific role in regulating Germ cell survival.
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Meiotic Germ Cells antagonize mesonephric cell migration and testis cord formation in mouse gonads
Development (Cambridge England), 2003Co-Authors: Humphrey H C Yao, Leo Dinapoli, Blanche CapelAbstract:The developmental fate of primordial Germ Cells in the mammalian gonad depends on their environment. In the XY gonad, Sry induces a cascade of molecular and cellular events leading to the organization of testis cords. Germ Cells are sequestered inside testis cords by 12.5 dpc where they arrest in mitosis. If the testis pathway is not initiated, Germ Cells spontaneously enter meiosis by 13.5 dpc, and the gonad follows the ovarian fate. We have previously shown that some testis-specific events, such as mesonephric cell migration, can be experimentally induced into XX gonads prior to 12.5 dpc. However, after that time, XX gonads are resistant to the induction of cell migration. In current experiments, we provide evidence that this effect is dependent on XX Germ Cells rather than on XX somatic Cells. We show that, although mesonephric cell migration cannot be induced into normal XX gonads at 14.5 dpc, it can be induced into XX gonads depleted of Germ Cells. We also show that when 14.5 dpc XX somatic Cells are recombined with XY somatic Cells, testis cord structures form normally; however, when XX Germ Cells are recombined with XY somatic Cells, cord structures are disrupted. Sandwich culture experiments suggest that the inhibitory effect of XX Germ Cells is mediated through short-range interactions rather than through a long-range diffusible factor. The developmental stage at which XX Germ Cells show a disruptive effect on the male pathway is the stage at which meiosis is normally initiated, based on the immunodetection of meiotic markers. We suggest that at the stage when Germ Cells commit to meiosis, they reinforce ovarian fate by antagonizing the testis pathway.