Licensing of Primordial Germ Cells for Gametogenesis Depends on Genital Ridge Signaling

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.

[1]  D. Page,et al.  Retinoic Acid Activates Two Pathways Required for Meiosis in Mice , 2014, PLoS genetics.

[2]  A. Oudenaarden,et al.  Validation of noise models for single-cell transcriptomics , 2014, Nature Methods.

[3]  D. Page,et al.  Tumor suppressor gene Rb is required for self-renewal of spermatogonial stem cells in mice , 2013, Proceedings of the National Academy of Sciences.

[4]  D. Page,et al.  Gata4 Is Required for Formation of the Genital Ridge in Mice , 2013, PLoS genetics.

[5]  M. De Felici,et al.  Minimal Concentrations of Retinoic Acid Induce Stimulation by Retinoic Acid 8 and Promote Entry into Meiosis in Isolated Pregonadal and Gonadal Mouse Primordial Germ Cells1 , 2013, Biology of reproduction.

[6]  Yi-Xun Liu,et al.  Disruption of genital ridge development causes aberrant primordial germ cell proliferation but does not affect their directional migration , 2013, BMC Biology.

[7]  W. Reik,et al.  The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells , 2012, Molecular cell.

[8]  M. Saitou,et al.  Primordial germ cells in mice. , 2012, Cold Spring Harbor perspectives in biology.

[9]  E. Laufer,et al.  Sonic hedgehog signaling during adrenal development , 2012, Molecular and Cellular Endocrinology.

[10]  P. Sharp,et al.  Mir-290–295 deficiency in mice results in partially penetrant embryonic lethality and germ cell defects , 2011, Proceedings of the National Academy of Sciences.

[11]  D. Page,et al.  Licensing of gametogenesis, dependent on RNA binding protein DAZL, as a gateway to sexual differentiation of fetal germ cells , 2011, Proceedings of the National Academy of Sciences.

[12]  Kamin J. Johnson,et al.  Uncovering Gene Regulatory Networks During Mouse Fetal Germ Cell Development1 , 2011, Biology of reproduction.

[13]  K. Molyneaux,et al.  BMP signaling controls formation of a primordial germ cell niche within the early genital ridges. , 2010, Developmental biology.

[14]  M. Saitou.  Germ cell specification in mice. , 2009, Current opinion in genetics & development.

[15]  D. Page,et al.  Germ Cell-Intrinsic and -Extrinsic Factors Govern Meiotic Initiation in Mouse Embryos , 2008, Science.

[16]  A. McMahon,et al.  Osr1 expression demarcates a multi-potent population of intermediate mesoderm that undergoes progressive restriction to an Osr1-dependent nephron progenitor compartment within the mammalian kidney. , 2008, Developmental biology.

[17]  Scott A. Rifkin,et al.  Imaging individual mRNA molecules using multiple singly labeled probes , 2008, Nature Methods.

[18]  Bin Zhou,et al.  Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart , 2008, Nature.

[19]  Ravi Sachidanandam,et al.  Developmentally Regulated piRNA Clusters Implicate MILI in Transposon Control , 2007, Science.

[20]  Anne E Carpenter,et al.  In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication , 2006, Nature Genetics.

[21]  J. Rossant,et al.  Retinoid Signaling Determines Germ Cell Fate in Mice , 2006, Science.

[22]  David C Page,et al.  Retinoic acid regulates sex-specific timing of meiotic initiation in mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[23]  E. Cho,et al.  Odd-skipped related 1 (Odd 1) is an essential regulator of heart and urogenital development. , 2005, Developmental biology.

[24]  S. Toyokuni,et al.  Spermatogenesis from epiblast and primordial germ cells following transplantation into postnatal mouse testis , 2004, Development.

[25]  S. Duncan,et al.  GATA4 is essential for formation of the proepicardium and regulates cardiogenesis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  K. Molyneaux,et al.  Transcriptional profiling identifies genes differentially expressed during and after migration in murine primordial germ cells. , 2004, Gene expression patterns : GEP.

[27]  C. Knudson,et al.  The pro-apoptotic gene Bax is required for the death of ectopic primordial germ cells during their migration in the mouse embryo , 2003, Development.

[28]  H. Yao,et al.  Meiotic germ cells antagonize mesonephric cell migration and testis cord formation in mouse gonads , 2003, Development.

[29]  D. Page,et al.  Sexual differentiation of germ cells in XX mouse gonads occurs in an anterior-to-posterior wave. , 2003, Developmental biology.

[30]  Andrew P McMahon,et al.  Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. , 2002, Developmental biology.

[31]  A. Mclaren,et al.  Sexually dimorphic development of mouse primordial germ cells: switching from oogenesis to spermatogenesis. , 2002, Development.

[32]  K. Molyneaux,et al.  Time-lapse analysis of living mouse germ cell migration. , 2001, Developmental biology.

[33]  N. Nakatsuji,et al.  Autonomous transition into meiosis of mouse fetal germ cells in vitro and its inhibition by gp130-mediated signaling. , 2001, Developmental biology.

[34]  Y. Matsui,et al.  Expression and intracellular localization of mouse Vasa-homologue protein during germ cell development , 2000, Mechanisms of Development.

[35]  G. Enders,et al.  Differentiation of murine premigratory primordial germ cells in culture. , 1999, Biology of reproduction.

[36]  B. Hogan,et al.  Bmp4 is required for the generation of primordial germ cells in the mouse embryo. , 1999, Genes & development.

[37]  D. Page,et al.  The Dazh gene is expressed in male and female embryonic gonads before germ cell sex differentiation. , 1998, Biochemical and biophysical research communications.

[38]  R. Lovell-Badge,et al.  Male-specific cell migration into the developing gonad , 1997, Current Biology.

[39]  A. Mclaren,et al.  Entry of mouse embryonic germ cells into meiosis. , 1997, Developmental biology.

[40]  D. Page,et al.  Zfx mutation results in small animal size and reduced germ cell number in male and female mice. , 1997, Development.

[41]  P. Tam,et al.  The allocation of epiblast cells to ectodermal and germ-line lineages is influenced by the position of the cells in the gastrulating mouse embryo. , 1996, Developmental biology.

[42]  K. Morohashi,et al.  Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF‐1 , 1996, Genes to cells : devoted to molecular & cellular mechanisms.

[43]  P. Goodfellow,et al.  Expression of Sry, the mouse sex determining gene. , 1995, Development.

[44]  G. Enders,et al.  Developmentally regulated expression of a mouse germ cell nuclear antigen examined from embryonic day 11 to adult in male and female mice. , 1994, Developmental biology.

[45]  David Housman,et al.  WT-1 is required for early kidney development , 1993, Cell.

[46]  Peter Goodfellow,et al.  Circular transcripts of the testis-determining gene Sry in adult mouse testis , 1993, Cell.

[47]  L. Westergaard,et al.  Forskolin and the meiosis inducing substance synergistically initiate meiosis in fetal male germ cells , 1993, Molecular reproduction and development.

[48]  C. Wylie,et al.  Genital ridges exert long-range effects on mouse primordial germ cell numbers and direction of migration in culture. , 1990, Development.

[49]  P. Donovan,et al.  Migratory and postmigratory mouse primordial germ cells behave differently in culture , 1986, Cell.

[50]  S. Upadhyay,et al.  Germ cell differentiation in mouse adrenal glands. , 1983, The Journal of experimental zoology.

[51]  S. Upadhyay,et al.  Ectopic germ cells: natural model for the study of germ cell sexual differentiation. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[52]  W. Ożdżeński.  Differentiation of the genital ridges of mouse embryos in the kidney of adult mice. , 1972, Archives d'anatomie microscopique et de morphologie experimentale.

[53]  F. W. Brambell.  The Development and Morphology of the Gonads of the Mouse.--Part I. The Morphogenesis of the Indifferent Gonad and of the Ovary , 1927 .

[54]  L. Looijenga,et al.  The distribution and behavior of extragonadal primordial germ cells in Bax mutant mice suggest a novel origin for sacrococcygeal germ cell tumors. , 2008, The International journal of developmental biology.

[55]  B. Capel,et al.  Sry induces cell proliferation in the mouse gonad. , 2000, Development.