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.

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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