title: Retinoic acid signaling is dispensable for somatic development and function in the mammalian ovary.
abstract: Retinoic acid (RA) is a potent inducer of cell differentiation and plays an essential role in sex-specific germ cell development in the mammalian gonad. RA is essential for male gametogenesis and hence fertility. However, RA can also disrupt sexual cell fate in somatic cells of the testis, promoting transdifferentiation of male Sertoli cells to female granulosa-like cells when the male sexual regulator Dmrt1 is absent. The feminizing ability of RA in the Dmrt1 mutant somatic testis suggests that RA might normally play a role in somatic cell differentiation or cell fate maintenance in the ovary. To test for this possibility we disrupted RA signaling in somatic cells of the early fetal ovary using three genetic strategies and one pharmaceutical approach. We found that deleting all three RA receptors (RARs) in the XX somatic gonad at the time of sex determination did not significantly affect ovarian differentiation, follicle development, or female fertility. Transcriptome analysis of adult triple mutant ovaries revealed remarkably little effect on gene expression in the absence of somatic RAR function. Likewise, deletion of three RA synthesis enzymes (Aldh1a1-3) at the time of sex determination did not masculinize the ovary. A dominant-negative RAR transgene altered granulosa cell proliferation, likely due to interference with a non-RA signaling pathway, but did not prevent granulosa cell specification and oogenesis or abolish fertility. Finally, culture of fetal XX gonads with an RAR antagonist blocked germ cell meiotic initiation but did not disrupt sex-biased gene expression. We conclude that RA signaling, although crucial in the ovary for meiotic initiation, is not required for granulosa cell specification, differentiation, or reproductive function.
authors.affiliation: Department of Genetics, Cell Biology, and Development, and Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Minkina
authors.affiliation: Department of Genetics, Cell Biology, and Development, and Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Robin E
authors.initials: RE
authors.lastname: Lindeman
authors.affiliation: Department of Genetics, Cell Biology, and Development, and Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Micah D
authors.initials: MD
authors.lastname: Gearhart
authors.affiliation: Université Cote d'Azur, Inserm, CNRS, iBV, F-06108 Nice, France.
authors.forename: Anne-Amandine
authors.initials: AA
authors.lastname: Chassot
authors.affiliation: Université Cote d'Azur, Inserm, CNRS, iBV, F-06108 Nice, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Chaboissier
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS (UMR7104), INSERM U964, Université de Strasbourg, F-67404 Illkirch, France.
authors.forename: Norbert B
authors.initials: NB
authors.lastname: Ghyselinck
authors.affiliation: Department of Genetics, Cell Biology, and Development, and Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, USA; University of Minnesota Masonic Cancer Center, Minneapolis, MN 55455, USA.
authors.forename: Vivian J
authors.initials: VJ
authors.lastname: Bardwell
authors.affiliation: Department of Genetics, Cell Biology, and Development, and Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, USA; University of Minnesota Masonic Cancer Center, Minneapolis, MN 55455, USA. Electronic address: zarko001@umn.edu.
authors.forename: David
authors.initials: D
authors.lastname: Zarkower
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D019070:Cell Lineage / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000196:embryology / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055786:Gene Knockout Techniques; D005799:Genes, Dominant; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008322:Mammals; D008540:Meiosis / Q000187:drug effects; D008650:Mesonephros / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D051379:Mice; D010053:Ovary / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology; D019849:Sex Determination Processes / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D046509:Tissue Culture Techniques; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: C423184:BMS 189453; D007527:Isoenzymes; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase
keywords: DMRT1; Granulosa; Ovary; Retinoic acid; Sertoli