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Germ cell specific overactivation of WNT/?catenin signalling has no effect on folliculogenesis but causes fertility defects due to abnormal foetal development.

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/?catenin 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 ?catenin 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 (Ctnnb1(ex3)cko) showed no defects in ovarian functions, oocytes, ovulation and early embryonic development. However, breeding of the Ctnnb1(ex3)cko 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/?catenin 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.

SUBMITTER: Kumar M

PROVIDER: S-EPMC4893675 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Germ cell specific overactivation of WNT/βcatenin signalling has no effect on folliculogenesis but causes fertility defects due to abnormal foetal development.

Kumar Manish M Camlin Nicole J NJ Holt Janet E JE Teixeira Jose M JM McLaughlin Eileen A EA Tanwar Pradeep S PS

Scientific reports 20160606

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 ...[more]

PMID: 27265527

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Project description:BackgroundCanonical WNT signalling plays a critical role in the regulation of ovarian development; mis-regulation of this key pathway in the adult ovary is associated with subfertility and tumourigenesis. The roles of Adenomatous polyposis coli 2 (APC2), a little-studied WNT signalling pathway regulator, in ovarian homeostasis, fertility and tumourigenesis have not previously been explored. Here, we demonstrate essential roles of APC2 in regulating ovarian WNT signalling and ovarian homeostasis.MethodsA detailed analysis of ovarian histology, gene expression, ovulation and hormone levels was carried out in 10 week old and in aged constitutive APC2-knockout (Apc2-/-) mice (mixed background). Statistical significance for qRT-PCR data was determined from 95% confidence intervals. Significance testing was performed using 2-tailed Student's t-test, when 2 experimental cohorts were compared. When more were compared, ANOVA test was used, followed by a post-hoc test (LSD or Games-Howell). P-values of < 0.05 were considered statistically significant.ResultsAPC2-deficiency resulted in activation of ovarian WNT signalling and sub-fertility driven by intra-ovarian defects. Follicular growth was perturbed, resulting in a reduced rate of ovulation and corpora lutea formation, which could not be rescued by administration of gonadotrophins. Defects in steroidogenesis and follicular vascularity contributed to the subfertility phenotype. Tumour incidence was assessed in aged APC2-deficient mice, which also carried a hypomorphic Apc allele. APC2-deficiency in these mice resulted in predisposition to granulosa cell tumour (GCT) formation, accompanied by acute tumour-associated WNT-signalling activation and a histologic pattern and molecular signature seen in human adult GCTs.ConclusionsOur work adds APC2 to the growing list of WNT-signalling members that regulate ovarian homeostasis, fertility and suppress GCT formation. Importantly, given that the APC2-deficient mouse develops tumours that recapitulate the molecular signature and histological features of human adult GCTs, this mouse has excellent potential as a pre-clinical model to study ovarian subfertility and transitioning to GCT, tumour biology and for therapeutic testing.

Dataset Information

Germ cell specific overactivation of WNT/?catenin signalling has no effect on folliculogenesis but causes fertility defects due to abnormal foetal development.

Publications

Germ cell specific overactivation of WNT/βcatenin signalling has no effect on folliculogenesis but causes fertility defects due to abnormal foetal development.

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