Abstract
All the major components of the WNT signalling pathway are expressed in female germ cells and embryos. However, their functional relevance in oocyte biology is currently unclear. We examined ovaries collected from TCFGFP mice, a well-known Wnt reporter mouse model, and found dynamic changes in the Wnt/βcatenin signalling activity during different stages of oocyte development and maturation. To understand the functional importance of Wnt signalling in oocytes, we developed a mouse model with the germ cell-specific constitutive activation of βcatenin using cre recombinase driven by the DEAD (Asp-Glu-Ala-Asp) box protein 4 (Ddx4) gene promoter. Histopathological and functional analysis of ovaries from these mutant mice (Ctnnb1ex3cko) showed no defects in ovarian functions, oocytes, ovulation and early embryonic development. However, breeding of the Ctnnb1ex3cko female mice with males of known fertility never resulted in birth of mutant pups. Examination of uteri from time pregnant mutant females revealed defects in ectoderm differentiation leading to abnormal foetal development and premature death. Collectively, our work has established the role of active WNT/βcatenin signalling in oocyte biology and foetal development, and provides novel insights into the possible mechanisms of complications in human pregnancy such as repeated spontaneous abortion, sudden intrauterine unexpected foetal death syndrome and stillbirth.
Highlights
Junctional complexes and infertility[4]
Similar genetic alterations in the CTNNB1 and Adenomatous Polyposis Coli (APC) genes are present in human Sertoli cell tumour patients[10,11], suggesting that deregulated WNT signalling is involved in the pathogenesis of testicular cancer
To determine the physiological activity of WNT signalling during follicular development, we examined ovaries from a well-characterized Wnt reporter mouse model, TCFGFP
Summary
Junctional complexes and infertility[4]. Similar genetic alterations in the CTNNB1 and APC genes are present in human Sertoli cell tumour patients[10,11], suggesting that deregulated WNT signalling is involved in the pathogenesis of testicular cancer. Similar to WNT4, Frizzled[4], a known receptor for WNT ligands, is expressed in the mouse ovary and its loss causes impairment of corpus lutea development and infertility without affecting follicular formation and functions[17]. Activation of PI3K signalling by deleting Pten in these mice results in the development of a highly aggressive and metastatic form of ovarian stromal tumours[19]. These findings highlight the importance of the WNT pathway in stromal cells of the ovary. To further understand the requirement of WNT signalling in oocyte biology, we developed a mouse model with overactive βcatenin in female germ cells and showed that abnormal WNT/βcatenin signalling leads to defects in female fertility
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