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APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression
Noha-Ehssan Mohamed1,2,3, Trevor Hay1, Karen R Reed1
1European Cancer Stem Cell Research Institute, Cardiff University School of Biosciences, Hadyn Ellis Building, Maindy, Road, Cardiff, CF24 4HQ, UK.
Background:
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. 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.
Methods:
A 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.
Results:
APC2-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.
Conclusions:
Our 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.
Insights
Adenomatous polyposis coli 2 (APC2) deficiency disrupts ovarian WNT signaling, causing subfertility and granulosa cell tumors (GCTs) in mice. This APC2-deficient mouse model is valuable for studying ovarian health and GCT development.
Area of Science:
- Reproductive biology
- Molecular oncology
- Genetics
Background:
- Canonical WNT signaling is crucial for ovarian development and homeostasis.
- Dysregulation of WNT signaling in the adult ovary is linked to subfertility and tumorigenesis.
- The role of Adenomatous polyposis coli 2 (APC2) in ovarian function and disease remains largely unexplored.
Purpose of the Study:
- To investigate the essential roles of APC2 in regulating ovarian WNT signaling and homeostasis.
- To determine the impact of APC2 deficiency on ovarian function, fertility, and tumor development.
- To establish a preclinical model for studying ovarian subfertility and granulosa cell tumors (GCTs).
Main Methods:
- Analysis of ovarian histology, gene expression, ovulation, and hormone levels in constitutive APC2-knockout (Apc2-/-) mice.
- Assessment of fertility, steroidogenesis, and follicular vascularity in APC2-deficient mice.
- Evaluation of tumor incidence and WNT signaling activation in aged APC2-deficient mice with a hypomorphic Apc allele.
Main Results:
- APC2 deficiency leads to activated ovarian WNT signaling and subfertility due to intra-ovarian defects.
- Perturbed follicular growth, reduced ovulation, and impaired corpora lutea formation were observed.
- APC2-deficient mice predisposed to granulosa cell tumors (GCTs) with molecular and histological features mirroring human GCTs.
Conclusions:
- APC2 is essential for maintaining ovarian homeostasis, fertility, and suppressing GCT formation.
- APC2 deficiency activates WNT signaling, contributing to subfertility and GCT development.
- The APC2-deficient mouse model effectively recapitulates human GCTs, offering a valuable tool for preclinical research and therapeutic testing.
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