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Human Molecular Genetics Advance Access originally published online on February 4, 2008
Human Molecular Genetics 2008 17(9):1278-1291; doi:10.1093/hmg/ddn036
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Discovery Research Laboratories, Research Division, Kirin Pharma Co., Ltd., 3 Miyahara-cho, Takasaki-shi, Gunma, 370-1295, Japan

* To whom correspondence should be addressed. Tel: +81 273469934; Fax: +81 273461971; Email: ktomizuka{at}kirin.co.jp

Received October 15, 2007; Accepted January 30, 2008

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.


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