Oocyte‐derived R‐spondin2 promotes ovarian follicle development

  • Yuan Cheng
    Program of Reproductive and Stem Cell Biology Stanford University School of Medicine Stanford California USA
  • Kazuhiro Kawamura
    Department of Obstetrics and Gynecology Akita University Akita Japan
  • Seido Takae
    Program of Reproductive and Stem Cell Biology Stanford University School of Medicine Stanford California USA
  • Masashi Deguchi
    Program of Reproductive and Stem Cell Biology Stanford University School of Medicine Stanford California USA
  • Qing Yang
    Program of Reproductive and Stem Cell Biology Stanford University School of Medicine Stanford California USA
  • Calvin Kuo
    Program of Reproductive and Stem Cell Biology Stanford University School of Medicine Stanford California USA
  • Aaron J. W. Hsueh
    Program of Reproductive and Stem Cell Biology Stanford University School of Medicine Stanford California USA

Bibliographic Information

Published
2013-02-13
Resource Type
journal article
Rights Information
  • http://onlinelibrary.wiley.com/termsAndConditions#vor
DOI
  • 10.1096/fj.12-223412
Publisher
Wiley

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<jats:p> R‐spondin proteins are adult stem cell growth factors capable of stimulating gut development by activating LGR4, 5, and 6 receptors to promote Wnt signaling. Although multiple Wnt ligands and cognate Frizzled receptors are expressed in the ovary, their physiological roles are unclear. Based on bioinformatic and <jats:italic>in situ</jats:italic> hybridization analyses, we demonstrated the exclusive expression of <jats:italic>R‐spondin</jats:italic> 2 in oocytes of ovarian follicles. In cultured somatic cells from preantral follicles, R‐spondin2 treatment (ED <jats:sub>50</jats:sub> : 3 ng/ml) synergized with Wnt3a to stimulate Wnt signaling. In cultured ovarian explants from prepubertal mice containing preantral follicles, treatment with R‐spondin2, similar to follicle stimulating hormone, promoted the development of primary follicles to the secondary stage. <jats:italic>In vivo</jats:italic> administration of an R‐spondin agonist stimulated the development of primary follicles to the antral stage in both immature mice and gonadotropin releasing hormone antagonist‐treated adult mice. Subsequent treatment with gonadotropins allowed the generation of mature oocytes capable of undergoing early embryonic development and successful pregnancy. Furthermore, R‐spondin agonist treatment of immune‐deficient mice grafted with human cortical fragments stimulated the development of primary follicles to the secondary stage. Thus, oocyte‐derived R‐spondin2 is a paracrine factor essential for primary follicle development, and R‐spondin agonists could provide a new treatment regimen for infertile women with low responses to the traditional gonadotropin therapy.—Cheng, Y., Kawamura, K., Takae, S., Deguchi, M., Yang, Q., Kuo, C., Hsueh, A. J. W. Oocyte‐derived R‐spondin2 promotes ovarian follicle development. <jats:italic>FASEB J.</jats:italic> 27, 2175–2184 (2013). <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://www.fasebj.org">www.fasebj.org</jats:ext-link> </jats:p>

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