title: Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells.
abstract: The discovery that the SRY gene induces male sex in humans and other mammals led to speculation about a possible equivalent for female sex. However, only partial effects have been reported for candidate genes experimentally tested so far. Here we demonstrate that inactivation of two ovarian somatic factors, Wnt4 and Foxl2, produces testis differentiation in XX mice, resulting in the formation of testis tubules and spermatogonia. These genes are thus required to initiate or maintain all major aspects of female sex determination in mammals. The two genes are independently expressed and show complementary roles in ovary morphogenesis. In addition, forced expression of Foxl2 impairs testis tubule differentiation in XY transgenic mice, and germ cell-depleted XX mice lacking Foxl2 and harboring a Kit mutation undergo partial female-to-male sex reversal. The results are all consistent with an anti-testis role for Foxl2. The data suggest that the relative autonomy of the action of Foxl2, Wnt4 and additional ovarian factor(s) in the mouse should facilitate the dissection of their respective contributions to female sex determination.
authors.affiliation: Laboratory of Genetics, NIA/NIH-IRP, Baltimore, USA. chris11@helix.nih.gov
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.forename: Emanuele
authors.initials: E
authors.lastname: Pelosi
authors.forename: Joseph
authors.initials: J
authors.lastname: Tran
authors.forename: Maria
authors.initials: M
authors.lastname: Colombino
authors.forename: Eric
authors.initials: E
authors.lastname: Douglass
authors.forename: Timur
authors.initials: T
authors.lastname: Nedorezov
authors.forename: Antonio
authors.initials: A
authors.lastname: Cao
authors.forename: Antonino
authors.initials: A
authors.lastname: Forabosco
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D012734:Disorders of Sex Development; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D010053:Ovary / Q000166:cytology / Q000196:embryology; D011247:Pregnancy; D019849:Sex Determination Processes; D012733:Sex Differentiation; D013737:Testis / Q000166:cytology / Q000196:embryology; D051153:Wnt Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D060528:Wnt4 Protein
chemical_list: D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse