Elucidation of the biological roles of Wnt5a signaling in follicle development
Follicle health is determined by an array of endocrine, paracrine and autocrine factors. Pituitary gonadotropins (LH and FSH) are major drivers of follicle development, but their actions are modulated by local hormones and growth factors. The WNT family of secreted glycoproteins are signaling molecules that act to modulate and coordinate follicular responses to the gonadotropins, and whose activities are indispensable for ovarian function and female fertility. WNTs are normally categorized according to pathway(s) via which they signal. The role of canonical WNT members and components such as CTNNB1, WNT4, WNT2, FZD4 and FZD1 is well established during follicle development in rodents. Whether WNTs play similar roles in monovular species remains essentially unknown. Moreover, the role of non-canonical WNTs in the rodent ovary is unclear. The objectives of the present thesis were (1) to elucidate the hormonal regulation of WNT5a expression and the physiological role of WNT5a in bovine granulosa cells in vitro and (2) to identify the physiological roles of WNT5a in the mouse ovary by conditional gene inactivation. The results of this thesis are presented in two articles. In the first article, the role of WNT5a in bovine granulosa cells was investigated in vitro. We found that WNT5A is a negative regulator of FSH-stimulated granulosa cell steroidogenesis, and that it acts by suppressing canonical WNT signaling activity and inducing the noncanonical MAPK8/JUN pathway. In the second article, we generated granulosa-specific knockout mouse models to examine the roles of two non-canonical WNTs, WNT5a and WNT11, in different stages of the follicular development. Our results showed that WNT5a is required for normal female fertility, follicle development and ovarian steroidogenesis, and is an antagonist of gonadotropin responsiveness that acts via the suppression of canonical WNT signaling. However we did not observe any significant defects in fertility of WNT11 knockout mice. Together, our work demonstrates that WNT5a is essential for normal follicle development and acts to inhibit differentiation in granulosa cells. In overview, we provided a novel and comprehensive investigation, using multiple models and techniques, to determine the mechanisms by which WNT5a regulates follicle development.
WNT5a Knock-out mouse Cow Follicle development Ovarian steroidogenesis Granulosa cells