title: R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling.
abstract: In mammals, female development has traditionally been considered a default process in the absence of the testis-determining gene, Sry. Recently, it has been documented that the gene for R-spondin1 (RSPO1), a novel class of soluble activator for Wnt/beta-catenin signaling, is mutated in two Italian families with female-to-male (XX) sex reversal. To elucidate the role of Rspo1 as a candidate female-determining gene in a mouse model, we generated Rspo1-null (Rspo1(-/-)) mice and found that Rspo1(-/-) XX mice displayed masculinized features including pseudohermaphroditism in genital ducts, depletion of fetal oocytes, male-specific coelomic vessel formation and ectopic testosterone production in the ovaries. Thus, although Rspo1 is required to fully suppress the male differentiation program and to maintain germ cell survival during the development of XX gonads, the loss of its activity has proved to be insufficient to cause complete XX sex reversal in mice. Interestingly, these partial sex-reversed phenotypes of Rspo1(-/-) XX mice recapitulated those of previously described Wnt-4(-/-) XX mice. In accordance with this finding, the expression of Wnt-4 and its downstream genes was deregulated in early Rspo1(-/-) XX gonads, suggesting that Rspo1 may participate in suppressing the male pathway in the absence of Sry and maintaining oocyte survival through positively regulating Wnt-4 signaling.
authors.affiliation: Discovery Research Laboratories, Research Division, Kirin Pharma Co., Ltd., Takasaki-shi, Gunma, 370-1295, Japan. ktomizuka@kirin.co.jp
authors.forename: Kazuma
authors.initials: K
authors.lastname: Tomizuka
authors.forename: Kaori
authors.initials: K
authors.lastname: Horikoshi
authors.forename: Rina
authors.initials: R
authors.lastname: Kitada
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Sugawara
authors.forename: Yumi
authors.initials: Y
authors.lastname: Iba
authors.forename: Ayako
authors.initials: A
authors.lastname: Kojima
authors.forename: Akiko
authors.initials: A
authors.lastname: Yoshitome
authors.forename: Kengo
authors.initials: K
authors.lastname: Yamawaki
authors.forename: Mikiko
authors.initials: M
authors.lastname: Amagai
authors.forename: Ayano
authors.initials: A
authors.lastname: Inoue
authors.forename: Takeshi
authors.initials: T
authors.lastname: Oshima
authors.forename: Makoto
authors.initials: M
authors.lastname: Kakitani
mesh_terms: D000818:Animals; D012734:Disorders of Sex Development / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005298:Fertility; D018507:Gene Expression Regulation, Developmental; D006729:Hormones, Ectopic / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009865:Oocytes / Q000166:cytology; D010053:Ovary / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D012733:Sex Differentiation; D015398:Signal Transduction; D013045:Species Specificity; D013739:Testosterone / Q000378:metabolism; D019699:Thrombospondins / Q000235:genetics* / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060528:Wnt4 Protein
chemical_list: D006729:Hormones, Ectopic; C518903:RSPO1 protein, mouse; D019699:Thrombospondins; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D013739:Testosterone