This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Folliculogenesis and oogenesis are complex processes which occur in the ovary and result in the production of fertilizable female germ cells. These processes require proper intercellular communication between many cell types including oocyte, granulosa, theca, and luteal cells within the ovary. Many intraovarian growth factors and endocrine factors such as insulin-like growth factor, epidermal growth factor, steroids, members of the transforming growth factor b family, the Wnt/Frizzled family, and gonadotropins are involved in these processes, affecting female reproduction. Here we propose that the hedgehog (Hh) signaling pathway, one of the major signaling pathways in driving cell proliferation and directing cell differentiation during embryonic and postnatal development, will play a role in folliculogenesis and oogenesis to regulate female fertility in mammals. There are many components of the Hh signaling pathway. In this proposal, we will focus on characterization of the roles of patched-1 (Ptc) and suppressor of fused (Sufu), two negative regulators of Hh signaling, in the ovary. Ptc is expressed in oocytes and theca cells in mouse ovary. Mice containing a natural occurring Ptc mutation (Ptcmes) display female sterility. Sufu is also highly expressed in mouse oocytes. Putative Gli DNA response elements are present in the promoters of Growth Differentiation Factor-9 (GDF-9) and cytochrome P450 17alpha-hydroxylase (Cyp17), which are known to play an important role in normal ovarian functions. Based on this information, we hypothesized that Hh signaling molecules Ptc and Sufu will play a role in folliculogenesis and oogenesis likely by regulating GDF-9 and Cyp17 expression in oocytes or thecal cells, affecting female fertility in mammals. Genetically modified Ptc and Sufu mouse models will be used to determine their ovarian roles in this study.
The specific aims are to (1) Characterize the ovarian phenotypes of sterile Ptc mutation mice carrying a spontaneous mesenchymal dysplasia (mes) mutation (Ptcmes/mes);and (2) Investigate the synergistic effects of Ptc and Sufu in the ovaries from Sufu+/-;Ptcmes/mes mutant mice. Fertility analysis in combination with morphological, histological, and molecular analyses will be performed to characterize ovarian phenotypes of these Sufu and Ptc mutant mice. It is expected that deletion of Ptc and/or Sufu will mimic ectopic Hh signaling in oocytes and/or thecal cells to stimulate their growth or proliferation, result in aberrant folliculogenesis and oogenesis, and eventually lead to female infertility. Introduction of a mutant Sufu allele into Ptcmes/mes mice will cause more severe ovarian phenotypes than Ptcmes/mes alone. The goal of this study is to explore whether Hh signaling is functional in the ovary. This study would substantially advance our knowledge about ovarian function and female fertility. Knowledge gained from this study could be used in diagnosis and treatment of female idiopathic infertility.
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