Journal Article

R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling

Kazuma Tomizuka, Kaori Horikoshi, Rina Kitada, Yuriko Sugawara, Yumi Iba, Ayako Kojima, Akiko Yoshitome, Kengo Yamawaki, Mikiko Amagai, Ayano Inoue, Takeshi Oshima and Makoto Kakitani

in Human Molecular Genetics

Volume 17, issue 9, pages 1278-1291
Published in print May 2008 | ISSN: 0964-6906
Published online February 2008 | e-ISSN: 1460-2083 | DOI:
R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling

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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/β-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.

Journal Article.  9352 words.  Illustrated.

Subjects: Genetics and Genomics

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