Regulation and Regulatory Role of WNT Signaling in Potentiating FSH Action during Bovine Dominant Follicle Selection

Abstract

Follicular development occurs in wave like patterns in monotocous species such as cattle and humans and is regulated by a complex interaction of gonadotropins with local intrafollicular regulatory molecules. To further elucidate potential mechanisms controlling dominant follicle selection, granulosa cell RNA harvested from F1 (largest) and F2 (second largest) follicles isolated at predeviation (PD) and onset of diameter deviation (OD) stages of the first follicular wave was subjected to preliminary RNA transcriptome analysis. Expression of numerous WNT system components was observed. Hence experiments were performed to test the hypothesis that WNT signaling modulates FSH action on granulosa cells during follicular waves. Abundance of mRNA for WNT pathway members was evaluated in granulosa cells harvested from follicles at emergence (EM), PD, OD and early dominance (ED) stages of the first follicular wave. In F1 follicles, abundance of CTNNB1 and DVL1 mRNAs was higher and AXIN2 mRNA was lower at ED versus EM stages and DVL1 and FZD6 mRNAs were higher and AXIN2 mRNA was lower in F1 versus F2 follicle at the ED stage. Bovine granulosa cells were treated in vitro with increasing doses of the WNT inhibitor IWR-1+/− maximal stimulatory dose of FSH. IWR-1 treatment blocked the FSH-induced increase in granulosa cell numbers and reduced the FSH-induced increase in estradiol. Granulosa cells were also cultured in the presence or absence of FSH +/− IWR-1 and hormonal regulation of mRNA for WNT pathway members and known FSH targets determined. FSH treatment increased CYP19A1, CCND2, CTNNB1, AXIN2 and FZD6 mRNAs and the stimulatory effect on CYP19A1 mRNA was reduced by IWR-1. In contrast, FSH reduced CARTPT mRNA and IWR-1 partially reversed the inhibitory effect of FSH. Results support temporal and hormonal regulation and a potential role for WNT signaling in potentiating FSH action during dominant follicle selection.

Tankyrase inhibition regulates corpus luteum development and luteal function in gonadotropin‐treated rats

“…The abundance of Wnt members in growing follicles increases after human Chorionic gonadotropin administration in rodents (Hsieh, Mulders, Friis, Dharmarajan, & Richards, ). The role of WNT regulating the function of FSH on cattle follicular cells has also been described (Abedini, Zamberlam, Boerboom, & Price, ; Gupta et al, ). The importance of Wnt signaling in the ovary is demonstrated by the phenotype associated with Wnt4 ovarian conditional‐knockout mice, which exhibit a 75% reduction in antral follicles that is probably due to increased follicular atresia (Boyer, Lapointe et al, ).…”

“…The abundance of Wnt members in growing follicles increases after human Chorionic gonadotropin administration in rodents (Hsieh, Mulders, Friis, Dharmarajan, & Richards, 2003). The role of WNT regulating the function of FSH on cattle follicular cells has also been described (Abedini, Zamberlam, Boerboom, & Price, 2015;Gupta et al, 2014).…”

The role of WNT signaling in adult ovarian folliculogenesis

“…Canonical WNT signaling is governed by the interaction of β-catenin with other molecules to regulate cellular decisions related to proliferation, differentiation, and morphogenesis (Willert & Jones 2006, Komiya & Habas 2008, Angers & Moon 2009). A series of studies have identified the expression and regulation of WNT ligands and downstream WNT signaling components in the developing follicle and corpus luteum of rats, mice, humans, and cattle (Hsieh et al 2002, Ricken et al 2002, Harwood et al 2008, Wang et al 2009, Castanon et al 2012, Gupta et al 2014) (Table 1). However, characterization of specific WNT molecules during folliculogenesis has been focused primarily on Wnt2 /WNT2 and Wnt4 /WNT4 in mice, rats and humans, although recent studies have unveiled contributions of frizzled receptor agonist, WNT3A in follicular development and steroid production of mice and rats (Li et al 2014, Stapp et al 2014).…”

Effect of single dose follicle stimulating hormone on follicular aspiration, in vitro fertilization and pregnancy rate

“…Follicular development is related to the transient increase of serum FSH that promotes the emergence of small follicles (Gupta et al, 2014). However, the decreasing concentration of serum FSH disrupts the development of the subordinate follicles that enter atresia and interrupts the selection of new subordinate follicles.…”

“…However, the decreasing concentration of serum FSH disrupts the development of the subordinate follicles that enter atresia and interrupts the selection of new subordinate follicles. A single follicle continues development (growth) to ovulatory size with an increase in the amount of estradiol synthesis, since the subordinate follicles lose the ability to synthesize estradiol and die from follicular atresia (Adams et al, 2008;Gupta et al, 2014;Nasser et al, 1993).…”