WNT4 is required for normal ovarian follicle development and female fertility

Abstract

To study the role of WNT4 in the postnatal ovary, a mouse strain bearing a floxed Wnt4 allele was created and mated to the Amhr2(tm3(cre)Bhr) strain to target deletion of Wnt4 to granulosa cells. Wnt4(flox/-);Amhr2(tm3(cre)Bhr/+) mice had reduced ovary weights and produced smaller litters (P<0.05). Serial follicle counting demonstrated that Wnt4(flox/-);Amhr2(tm3(cre)Bhr/+) mice were born with a normal ovarian reserve and maintained normal numbers of small follicles until puberty but had only 25.2% of the normal number of healthy antral follicles. Some Wnt4(flox/-);Amhr2(tm3(cre)Bhr/+) mice had no antral follicles or corpora lutea and underwent premature follicle depletion. RT-PCR analyses of Wnt4(flox/-);Amhr2(tm3(cre)Bhr/+) granulosa cells and cultured granulosa cells that overexpress WNT4 demonstrated that WNT4 regulates the expression of Star, Cyp11a1, and Cyp19, steroidogenic genes previously identified as downstream targets of the WNT signaling effector CTNNB1. Decreased serum progesterone levels were found in immature, gonadotropin-treated Wnt4(flox/-);Amhr2(tm3(cre)Bhr/+) mice (P<0.05). WNT4- and CTNNB1-overexpressing cultured granulosa cells were analyzed by microarray for alterations in gene expression, which showed that WNT4 regulates additional genes involved in late follicle development via the WNT/CTNNB1 signaling pathway. Together, these data indicate that WNT4 is required for normal antral follicle development and may act by regulating granulosa cell functions including steroidogenesis.

Ovulation as danger signaling event of innate immunity

“…In this line is M a n u s c r i p t 8 the report on Wnt4 knock out mice showing disturbed follicle development and infertility (Boyer et al, 2010). In the late phase of the ovulatory event (Fig.…”

Secreted frizzled related proteins: Implications in cancers

“…Wnt ligands are widely expressed in the ovaries [73], are essential for ovarian follicular development and fertility [74], and also contribute to ovarian tumourigenesis through the canonical Wnt signalling pathway [75]. β-catenin, an essential component of the Wnt signalling pathway, contributes to ovarian endometrioid carcinomas [76,77].…”

Copy number variation analysis reveals additional variants contributing to endometriosis development

“…This locus contains markers located in or near the WNT4 gene, which plays an important role on the development of the female reproductive tract and steroidogenesis [37,38]. The literature emphasizes the role of the WNT4 as a regulator of cell proliferation and differentiation, in which the signaling pathway involves proteins that directly participate in both gene transcription and cell adhesion [39].…”