β-Catenin (CTNNB1) Promotes Preovulatory Follicular Development but Represses LH-Mediated Ovulation and Luteinization

Abstract

Wingless-type mouse mammary tumor virus integration site family (WNT)/beta-catenin (CTNNB1) pathway components are expressed in ovarian granulosa cells, direct female gonad development, and are regulated by the pituitary gonadotropins. However, the in vivo functions of CTNNB1 during preovulatory follicular development, ovulation, and luteinization remain unclear. Using a mouse model Ctnnb1((Ex3)fl/fl);Cyp19-Cre (Ctnnb1((Ex3)gc-/-)), expressing dominant stable CTNNB1 in granulosa cells of small antral and preovulatory follicles, we show that CTNNB1 facilitates FSH-induced follicular growth and decreases the follicle atresia (granulosa cell apoptosis). At the molecular level, WNT signaling and FSH synergistically promote the expression of genes required for cell proliferation and estrogen biosynthesis, but decrease FOXO1, which negatively regulates proliferation and steroidogenesis. Conversely, dominant stable CTNNB1 represses LH-induced oocyte maturation, ovulation, luteinization, and progesterone biosynthesis. Specifically, granulosa cells in the Ctnnb1((Ex3)gc)(-/-) mice showed compromised responses to the LH surge and decreased levels of the epidermal growth factor-like factors (Areg and Ereg) that in vivo and in vitro mediate LH action. One underlying mechanism by which CTNNB1 prevents LH responses is by reducing phosphorylation of cAMP-responsive element-binding protein, which is essential for the expression of Areg and Ereg. By contrast, depletion of Ctnnb1 using the Ctnnb1(fl/fl);Cyp19-Cre mice did not alter FSH regulation of preovulatory follicular development or female fertility but dramatically enhanced LH induction of genes in granulosa cells in culture. Thus, CTNNB1 can enhance FSH and LH actions in antral follicles but overactivation of CTNNB1 negatively effects LH-induced ovulation and luteinization, highlighting the cell context-dependent and developmental stage-specific interactions of WNT/CTNNB1 pathway and G protein-coupled gonadotropin receptors in female fertility.

Differences in the transcriptional profiles of human cumulus cells isolated from MI and MII oocytes of patients with polycystic ovary syndrome

“…Three genes (CTNNB1, SFRP4, and TNIK) associated with the Wnt signaling pathway were identified in our study. It has recently been reported that the WNT/b-catenin signaling pathway plays a complicated role in ovulation, and as a Wnt antagonist, SFRP4 is an important marker of ovulation and luteinization (Fan et al 2010). Moreover, SFRP4 is expressed in human GCs and its expression, which is inhibited by LH/HCG, declines during late antral follicular growth (Maman et al 2011).…”

β-Catenin/Tcf signaling in murine oocytes identifies nonovulatory follicles

“…Recent evidence indicates that depleting b-catenin in granulosa cells of growing and pre-ovulatory follicles does not cause any overt effects in follicular development, ovulation, or luteinization (Fan et al 2010). The reason(s) why some granulosa and luteal cells, but not all, stain for lacZ remains to be elucidated.…”

“…This defect may be within the oocyte or follicle. It has been demonstrated that over-activation of b-catenin negatively affects LH-induced ovulation and luteinization (Fan et al 2010). It is also known that disruption of pituitary LH synthesis, LH receptor binding, or its downstream signaling pathways blocks ovulation and luteinization (Elvin & Matzuk 1998).…”

Effects of dietary quercetin on female fertility in mice: implication of transglutaminase 2

“…TG2 is present in the endometrial epithelium where it participates in adhesion and migratory events during embryo implantation (Fujimoto et al 1996; Kabir-Salmani et al 2005). In addition, TG2 regulates various signalling cascades, including the canonical β-catenin pathway (Beazley et al 2012) that has been implicated in regulating ovulation (Fan et al 2010; Usongo et al 2012). …”