title: DMRT1 prevents female reprogramming in the postnatal mammalian testis.
abstract: Sex in mammals is determined in the fetal gonad by the presence or absence of the Y chromosome gene Sry, which controls whether bipotential precursor cells differentiate into testicular Sertoli cells or ovarian granulosa cells. This pivotal decision in a single gonadal cell type ultimately controls sexual differentiation throughout the body. Sex determination can be viewed as a battle for primacy in the fetal gonad between a male regulatory gene network in which Sry activates Sox9 and a female network involving WNT/β-catenin signalling. In females the primary sex-determining decision is not final: loss of the FOXL2 transcription factor in adult granulosa cells can reprogram granulosa cells into Sertoli cells. Here we show that sexual fate is also surprisingly labile in the testis: loss of the DMRT1 transcription factor in mouse Sertoli cells, even in adults, activates Foxl2 and reprograms Sertoli cells into granulosa cells. In this environment, theca cells form, oestrogen is produced and germ cells appear feminized. Thus Dmrt1 is essential to maintain mammalian testis determination, and competing regulatory networks maintain gonadal sex long after the fetal choice between male and female. Dmrt1 and Foxl2 are conserved throughout vertebrates and Dmrt1-related sexual regulators are conserved throughout metazoans. Antagonism between Dmrt1 and Foxl2 for control of gonadal sex may therefore extend beyond mammals. Reprogramming due to loss of Dmrt1 also may help explain the aetiology of human syndromes linked to DMRT1, including disorders of sexual differentiation and testicular cancer.
authors.affiliation: Developmental Biology Center and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Clinton K
authors.initials: CK
authors.lastname: Matson
authors.forename: Mark W
authors.initials: MW
authors.lastname: Murphy
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.forename: Michael D
authors.initials: MD
authors.lastname: Griswold
authors.forename: Vivian J
authors.initials: VJ
authors.lastname: Bardwell
authors.forename: David
authors.initials: D
authors.lastname: Zarkower
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D054338:Cell Transdifferentiation; D005260:Female; D005262:Feminization / Q000235:genetics; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism; D012708:Sertoli Cells / Q000166:cytology / Q000378:metabolism; D012727:Sex Characteristics; D019849:Sex Determination Processes / Q000235:genetics / Q000502:physiology*; D012733:Sex Differentiation / Q000235:genetics / Q000502:physiology*; D013737:Testis / Q000166:cytology / Q000378:metabolism*; D013799:Theca Cells / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C110547:DMRT1 protein; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; D012333:RNA, Messenger; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D014157:Transcription Factors