title: DMRT1 protects male gonadal cells from retinoid-dependent sexual transdifferentiation.
abstract: Mammalian sex determination initiates in the fetal gonad with specification of bipotential precursor cells into male Sertoli cells or female granulosa cells. This choice was long presumed to be irreversible, but genetic analysis in the mouse recently revealed that sexual fates must be maintained throughout life. Somatic cells in the testis or ovary, even in adults, can be induced to transdifferentiate to their opposite-sex equivalents by loss of a single transcription factor, DMRT1 in the testis or FOXL2 in the ovary. Here, we investigate what mechanism DMRT1 prevents from triggering transdifferentiation. We find that DMRT1 blocks testicular retinoic acid (RA) signaling from activating genes normally involved in female sex determination and ovarian development and show that inappropriate activation of these genes can drive sexual transdifferentiation. By preventing activation of potential feminizing genes, DMRT1 allows Sertoli cells to participate in RA signaling, which is essential for reproduction, without being sexually reprogrammed.
authors.affiliation: Developmental Biology Center and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Minkina
authors.affiliation: Developmental Biology Center and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: Clinton K
authors.initials: CK
authors.lastname: Matson
authors.affiliation: Developmental Biology Center and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: Robin E
authors.initials: RE
authors.lastname: Lindeman
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS (UMR7104), INSERM U964, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Norbert B
authors.initials: NB
authors.lastname: Ghyselinck
authors.affiliation: Developmental Biology Center and Department of Genetics, Cell Biology, and Development, 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: Developmental Biology Center and Department of Genetics, Cell Biology, and Development, 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: D000818:Animals; D015153:Blotting, Western; D054338:Cell Transdifferentiation / Q000187:drug effects*; D005260:Female; D005455:Fluorescent Antibody Technique; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010053:Ovary / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000378:metabolism; D012708:Sertoli Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019849:Sex Determination Processes / Q000187:drug effects; D013737:Testis / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C110547:DMRT1 protein; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D014157:Transcription Factors