Meiosis Initiates In The Fetal Ovary Of Mice Lacking All Retinoic Acid Receptor Isotypes

Gametes are generated through a specialized cell differentiation process, meiosis which, in most mammals, is initiated in ovaries during fetal life. It is widely admitted that all-trans retinoic acid (ATRA) is the molecular signal triggering meiosis initiation in mouse female germ cells, but a genetic approach in which ATRA synthesis is impaired disputes this proposal. In the present study, we investigated the contribution of endogenous ATRA to meiosis by analyzing fetuses lacking all RARs ubiquitously, obtained through a tamoxifen-inducible cre recombinase-mediated gene targeting approach. Efficient ablation of RAR-coding genes was assessed by the multiple congenital abnormalities displayed by the mutant fetuses. Unexpectedly, their germ cells robustly expressed STRA8, REC8, SYCP1 and SYCP3, showing that RAR are actually dispensable up to the zygotene stage of meiotic prophase I. Thus our study goes against the current model according to which meiosis is triggered by endogenous ATRA in the developing ovary and revives the identification of the meiosis-preventing substance synthesized by CYP26B1 in the fetal testis.

[1]  G. Duester,et al.  Retinoic acid signaling pathways , 2019, Development.

[2]  Jace W. Jones,et al.  Two functionally redundant sources of retinoic acid secure spermatogonia differentiation in the seminiferous epithelium , 2019, Development.

[3]  A. Sinclair,et al.  Retinoic Acid Antagonizes Testis Development in Mice. , 2018, Cell reports.

[4]  H. Ohta,et al.  Bone morphogenetic protein and retinoic acid synergistically specify female germ‐cell fate in mice , 2017, The EMBO journal.

[5]  H. Kagechika,et al.  All trans-retinoic acid analogs promote cancer cell apoptosis through non-genomic Crabp1 mediating ERK1/2 phosphorylation , 2016, Scientific Reports.

[6]  J. Bowles,et al.  ALDH1A1 provides a source of meiosis-inducing retinoic acid in mouse fetal ovaries , 2016, Nature Communications.

[7]  A. Oudenaarden,et al.  A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary , 2015, PLoS genetics.

[8]  M. De Felici,et al.  Activin A accelerates the progression of fetal oocytes throughout meiosis and early oogenesis in the mouse. , 2015, Stem cells and development.

[9]  J. Bedő,et al.  RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis-regulatory elements , 2015, Nucleic acids research.

[10]  G. Duester,et al.  Mechanisms of retinoic acid signalling and its roles in organ and limb development , 2015, Nature Reviews Molecular Cell Biology.

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

[12]  J. Bowles,et al.  Control of mammalian germ cell entry into meiosis , 2014, Molecular and Cellular Endocrinology.

[13]  G. Duester,et al.  Resolving Molecular Events in the Regulation of Meiosis in Male and Female Germ Cells , 2013, Science Signaling.

[14]  C. Rochette-Egly,et al.  Vitamin A and retinoid signaling: genomic and nongenomic effects , 2013, Journal of Lipid Research.

[15]  D. Page,et al.  Oocyte differentiation is genetically dissociable from meiosis in mice , 2013, Nature Genetics.

[16]  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.

[17]  M. Vidal,et al.  PRC1 coordinates timing of sexual differentiation of female primordial germ cells , 2013, Nature.

[18]  Yan Cui,et al.  Retinoic acid derived from the fetal ovary initiates meiosis in mouse germ cells , 2013, Journal of cellular physiology.

[19]  J. Bowles,et al.  Precious Cargo: Regulation of Sex-Specific Germ Cell Development in Mice , 2012, Sexual Development.

[20]  Steven C. Munger,et al.  Temporal Transcriptional Profiling of Somatic and Germ Cells Reveals Biased Lineage Priming of Sexual Fate in the Fetal Mouse Gonad , 2012, PLoS genetics.

[21]  M. Griswold,et al.  Initiating Meiosis: The Case for Retinoic Acid1 , 2012, Biology of reproduction.

[22]  N. Frydman,et al.  Msx1 and Msx2 promote meiosis initiation , 2011, Development.

[23]  M. Griswold,et al.  DMRT1 promotes oogenesis by transcriptional activation of Stra8 in the mammalian fetal ovary. , 2011, Developmental biology.

[24]  M. Meistrich,et al.  Spermatogonial morphology and kinetics during testis development in mice: a high-resolution light microscopy approach. , 2011, Reproduction.

[25]  Hynek Wichterle,et al.  Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis , 2011, Genome Biology.

[26]  G. Duester,et al.  Sex-specific timing of meiotic initiation is regulated by Cyp26b1 independent of retinoic acid signalling. , 2011, Nature communications.

[27]  J. D. Engel,et al.  The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor*♦ , 2010, The Journal of Biological Chemistry.

[28]  J. Bowles,et al.  Sex determination in mammalian germ cells: extrinsic versus intrinsic factors. , 2010, Reproduction.

[29]  J. Tilly,et al.  Epigenetic status determines germ cell meiotic commitment in embryonic and postnatal mammalian gonads , 2010, Cell cycle.

[30]  H. Gronemeyer,et al.  Differential action on coregulator interaction defines inverse retinoid agonists and neutral antagonists. , 2009, Chemistry & biology.

[31]  A. Kocer,et al.  Germ cell sex determination in mammals , 2009, Molecular human reproduction.

[32]  M. Tsai,et al.  Identification of COUP-TFII Orphan Nuclear Receptor as a Retinoic Acid–Activated Receptor , 2008, PLoS biology.

[33]  P. Chambon,et al.  Apoptotic extinction of germ cells in testes of Cyp26b1 knockout mice. , 2007, Endocrinology.

[34]  Josephine Bowles,et al.  Retinoic acid, meiosis and germ cell fate in mammals , 2007, Development.

[35]  L. Luo,et al.  A global double‐fluorescent Cre reporter mouse , 2007, Genesis.

[36]  A. Bhandoola,et al.  Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. , 2007, Cell stem cell.

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

[38]  C. Glass,et al.  Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. , 2006, Genes & development.

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

[40]  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.

[41]  P. Chambon,et al.  Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. , 2006, Annual review of pharmacology and toxicology.

[42]  Fredy Sussman,et al.  Ligand recognition by RAR and RXR receptors: binding and selectivity. , 2005, Journal of medicinal chemistry.

[43]  Pierre Chambon,et al.  The nuclear receptor superfamily: a personal retrospect on the first two decades. , 2005, Molecular endocrinology.

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

[45]  E. Revenkova,et al.  Meiotic cohesin REC8 marks the axial elements of rat synaptonemal complexes before cohesins SMC1β and SMC3 , 2003, The Journal of cell biology.

[46]  G. Giuili,et al.  Murine spermatogonial stem cells: targeted transgene expression and purification in an active state , 2002, EMBO reports.

[47]  Peng Liu,et al.  Selective Cooperation between Fatty Acid Binding Proteins and Peroxisome Proliferator-Activated Receptors in Regulating Transcription , 2002, Molecular and Cellular Biology.

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

[49]  P. Chambon,et al.  A conditional floxed (loxP‐flanked) allele for the retinoic acid receptor gamma (RARγ) gene , 2002 .

[50]  P. Chambon,et al.  A conditional floxed (loxP‐flanked) allele for the retinoic acid receptor beta (RARβ) gene , 2002 .

[51]  P. Chambon,et al.  A conditional floxed (loxP‐flanked) allele for the retinoic acid receptor alpha (RARα) gene , 2002 .

[52]  H. Gronemeyer,et al.  Co-regulator recruitment and the mechanism of retinoic acid receptor synergy , 2002, Nature.

[53]  R. Evans,et al.  Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[54]  P. Chambon,et al.  Roles of retinoic acid receptors in early embryonic morphogenesis and hindbrain patterning. , 2001, Development.

[55]  G. Livera,et al.  Effects of retinoids on the meiosis in the fetal rat ovary in culture , 2000, Molecular and Cellular Endocrinology.

[56]  J. Ward,et al.  Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor β(δ) , 2000, Molecular and Cellular Biology.

[57]  R. Chandraratna,et al.  Recruitment of Nuclear Receptor Corepressor and Coactivator to the Retinoic Acid Receptor by Retinoid Ligands , 2000, The Journal of Biological Chemistry.

[58]  D. Levinthal,et al.  Distinct Roles for Cellular Retinoic Acid-binding Proteins I and II in Regulating Signaling by Retinoic Acid* , 1999, The Journal of Biological Chemistry.

[59]  H. Brismar,et al.  The Synaptonemal Complex Protein SCP3 Can Form Multistranded, Cross-striated Fibers In Vivo , 1998, The Journal of cell biology.

[60]  F. Conquet,et al.  Disruption of retinoid‐related orphan receptor β changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice , 1998, The EMBO journal.

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

[62]  P. Chambon,et al.  Role of the retinoic acid receptor beta (RARbeta) during mouse development. , 1997, The International journal of developmental biology.

[63]  G. Duester.  Involvement of Alcohol Dehydrogenase, Short-Chain Dehydrogenase/Reductase, Aldehyde Dehydrogenase, and Cytochrome P450 in the Control of Retinoid Signaling by Activation of Retinoic Acid Synthesis† , 1996 .

[64]  S. Nagpal,et al.  Identification and Functional Separation of Retinoic Acid Receptor Neutral Antagonists and Inverse Agonists* , 1996, The Journal of Biological Chemistry.

[65]  A. Mclaren,et al.  Germ cells and germ cell sex. , 1995, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[66]  N. Nakatsuji,et al.  Retinoic acid is a potent growth activator of mouse primordial germ cells in vitro. , 1995, Developmental biology.

[67]  M. Maden,et al.  Endogenous distribution of retinoids during normal development and teratogenesis in the mouse embryo , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.

[68]  P. Chambon,et al.  Mice deficient in cellular retinoic acid binding protein II (CRABPII) or in both CRABPI and CRABPII are essentially normal. , 1995, Development.

[69]  P. Chambon,et al.  Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. , 1994, Development.

[70]  P Chambon,et al.  The cellular retinoic acid binding protein I is dispensable. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[71]  P. Chambon,et al.  Retinoic acid receptors and cellular retinoid binding proteins. I. A systematic study of their differential pattern of transcription during mouse organogenesis. , 1990, Development.

[72]  P. Chambon,et al.  Specific spatial and temporal distribution of retinoic acid receptor gamma transcripts during mouse embryogenesis. , 1990, Development.

[73]  M. De Felici,et al.  Isolation of mouse primordial germ cells. , 1982, Experimental cell research.

[74]  A. Byskov,et al.  Induction of meiosis in fetal mouse testis in vitro. , 1976, Developmental biology.

[75]  K. Borum.  Oogenesis in the mouse. A study of the meiotic prophase. , 1961, Experimental cell research.

[76]  J. Bowles,et al.  Sexually dimorphic germ cell identity in mammals. , 2019, Current topics in developmental biology.

[77]  C. Hogarth,et al.  Germ Cell Commitment to Oogenic Versus Spermatogenic Pathway: The Role of Retinoic Acid. , 2016, Results and problems in cell differentiation.

[78]  J. Bowles,et al.  Regulation of germ cell meiosis in the fetal ovary. , 2012, The International journal of developmental biology.

[79]  P. Chambon,et al.  Retinoic acid metabolism and signaling pathways in the adult and developing mouse testis. , 2006, Endocrinology.

[80]  Martin Wehling,et al.  Nongenomic actions of steroid hormones , 2003, Nature Reviews Molecular Cell Biology.

[81]  F. Oerlemans,et al.  Normal development, growth and reproduction in cellular retinoic acid binding protein-I (CRABPI) null mutant mice. , 1994, Differentiation; research in biological diversity.