title: Sexual cell-fate reprogramming in the ovary by DMRT1.
abstract: Transcription factors related to the insect sex-determination gene doublesex (DMRT proteins) control sex determination and/or sexual differentiation in diverse metazoans and are implicated in transitions between sex-determining mechanisms during vertebrate evolution [1]. In mice, Dmrt1 is required for male gonadal differentiation in somatic cells and germ cells [2-4]. DMRT1 also maintains male gonadal sex: its loss, even in adults, can trigger sexual cell-fate reprogramming in which male Sertoli cells transdifferentiate into their female equivalents-granulosa cells-and testicular tissue reorganizes to a more ovarian morphology [5]. Here we use a conditional Dmrt1 transgene to show that Dmrt1 is not only necessary but also sufficient to specify male cell identity in the mouse gonad. DMRT1 expression in the ovary silenced the female sex-maintenance gene Foxl2 and reprogrammed juvenile and adult granulosa cells into Sertoli-like cells, triggering formation of structures resembling male seminiferous tubules. DMRT1 can silence Foxl2 even in the absence of the testis-determining genes Sox8 and Sox9. mRNA profiling found that DMRT1 activates many testicular genes and downregulates ovarian genes and single-cell RNA sequencing in transdifferentiating cells identified dynamically expressed candidate mediators of this process. Strongly upregulated genes were highly enriched on chromosome X, consistent with sexually antagonistic functions. This study provides an in vivo example of single-gene reprogramming of cell sexual identity. Our findings suggest a reconsideration of mechanisms involved in human disorders of sex development (DSDs) and empirically support evolutionary models in which loss or gain of Dmrt1 function promotes establishment of new vertebrate sex-determination systems.
authors: Department of Genetics, Cell Biology, and Development, Developmental Biology Center, and Masonic Cancer Center, University of Minnesota, 6-160 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455 USA.
authors: Robin E
authors: RE
authors: Lindeman
authors: Department of Genetics, Cell Biology, and Development, Developmental Biology Center, and Masonic Cancer Center, University of Minnesota, 6-160 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455 USA.
authors: Micah D
authors: MD
authors: Gearhart
authors: Department of Genetics, Cell Biology, and Development, Developmental Biology Center, and Masonic Cancer Center, University of Minnesota, 6-160 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455 USA.
authors: Anna
authors: A
authors: Minkina
authors: Department of Genetics, Cell Biology, and Development, Developmental Biology Center, and Masonic Cancer Center, University of Minnesota, 6-160 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455 USA.
authors: Anthony D
authors: AD
authors: Krentz
authors: Department of Genetics, Cell Biology, and Development, Developmental Biology Center, and Masonic Cancer Center, University of Minnesota, 6-160 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455 USA.
authors: Vivian J
authors: VJ
authors: Bardwell
authors: Department of Genetics, Cell Biology, and Development, Developmental Biology Center, and Masonic Cancer Center, University of Minnesota, 6-160 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455 USA. Electronic address: zarko001@umn.edu.
authors: David
authors: D
authors: Zarkower
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation; D065150:Cellular Reprogramming / Q000235:genetics* / Q000502:physiology*; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010053:Ovary / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism; D012708:Sertoli Cells / Q000166:cytology / Q000378:metabolism; D019849:Sex Determination Processes / Q000235:genetics* / Q000502:physiology*; D012733:Sex Differentiation; D059010:Single-Cell Analysis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014960:X Chromosome / Q000235:genetics
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; D055757:SOXE Transcription Factors; C498639:Sox8 protein, mouse; C527933:Sox9 protein, mouse; D014157:Transcription Factors