Abstract
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.
Highlights
Canonical 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
Adenomatous polyposis coli 2 (APC2) deficiency activates ovarian WNT signalling and upregulates Foxo1 expression As APC2 is a known regulator of canonical WNT signalling, we investigated whether dysregulated WNT signalling was mechanistically linked to the restriction in follicular growth in Apc2−/− ovaries
This study has revealed that APC2-deficiency activates WNT signalling in the ovary during early adulthood, which subsequently disrupts ovarian homeostasis and causes subfertility originating from an ovarian defect
Summary
Canonical 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. Ovarian amplification of Rspo1 [15], deletion of Wnt5a (antagonist of canonical WNT signalling) [16] or expression of dominant stable β-catenin [10, 17] all resulted in up-regulated ovarian WNT signalling and ovarian subfertility caused by disruption of follicle growth [16, 17], ovulation and luteinisation [10, 15]. Taken together, these findings indicate the importance of tight regulation of canonical WNT signalling in growing follicles
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