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Published on: June 17, 2014
Beta-catenin (CTNNB1) promotes preovulatory follicular development but represses LH-mediated ovulation and
Heng-Yu Fan1, Annalouise O'Connor, Manami Shitanaka
1Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
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.
Insights
The Wingless-type mouse mammary tumor virus integration site family (WNT)/beta-catenin (CTNNB1) pathway plays a dual role in ovarian function. While it supports follicle growth stimulated by FSH (follicle-stimulating hormone), overactivation impairs LH (luteinizing hormone)-induced ovulation and luteinization.
Area of Science:
- Reproductive biology
- Molecular endocrinology
- Cell signaling
Background:
- Wingless-type mouse mammary tumor virus integration site family (WNT)/beta-catenin (CTNNB1) pathway components are crucial for female gonad development.
- The precise in vivo roles of CTNNB1 in preovulatory follicular development, ovulation, and luteinization are not fully understood.
Purpose of the Study:
- To elucidate the in vivo functions of CTNNB1 during key stages of ovarian follicle development and function.
- To investigate the molecular mechanisms underlying CTNNB1's regulation of gonadotropin signaling in granulosa cells.
Main Methods:
- Utilized a conditional knockout mouse model (Ctnnb1((Ex3)fl/fl);Cyp19-Cre) to express dominant-stable CTNNB1 in granulosa cells.
- Analyzed follicular growth, atresia, gene expression, and hormonal responses to FSH and LH.
- Investigated molecular pathways including cAMP-responsive element-binding protein phosphorylation and epidermal growth factor-like factors.
Main Results:
- Dominant-stable CTNNB1 enhanced FSH-induced follicular growth and reduced granulosa cell apoptosis.
- Overactivated CTNNB1 repressed LH-induced oocyte maturation, ovulation, luteinization, and progesterone production.
- CTNNB1 modulated gene expression related to proliferation, estrogen biosynthesis, and steroidogenesis, partly via FOXO1 regulation.
- Impaired LH response in dominant-stable CTNNB1 granulosa cells was linked to reduced CREB phosphorylation and lower Areg/Ereg levels.
Conclusions:
- CTNNB1 exhibits context-dependent and stage-specific roles in ovarian function, enhancing FSH action but inhibiting LH action at high levels.
- Overactivation of CTNNB1 negatively impacts ovulation and luteinization, suggesting a critical balance for female fertility.
- Interactions between WNT/CTNNB1 signaling and gonadotropin receptors are vital for regulating granulosa cell function and female reproductive success.
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