WNT5A Enhances LH-Mediated Expression of HAS2 in Granulosa Cells

In adult ovary, WNT5A is involved in follicular responses to gonadotropins and necessary for ovarian follicle development. However, the mechanism by which gonadotropins regulate WNT5A and the role of WNT5A in modulating follicular responses to gonadotropins are unclear. In mice, we discovered that the expression of Wnt5a was increased in granulosa cells of mouse ovaries during ovulation, and regulated by gonadotropin-activated intra-ovarian cytokine interleukin 6 (IL6). Using human granulosa-like KGN cells, we confirmed that forskolin plus phorbol myristate acetate (PMA) which mimic the luteinizing hormone (LH) action induced the expression of WNT5A and cumulus expansion gene HAS2. However, this effect was suppressed by a NF-κB pathway inhibitor. Inhibition of NF-κB pathway also blocked the activation of WNT5A signaling components ROR2 and JNK. Moreover, exogenous WNT5A enhanced the expression of HAS2 in KGN cells through JNK and AKT signaling pathways. Knockdown of WNT5A expression by siRNA disrupted LH-mediated expression of HAS2. Our findings indicate that WNT5A could be a fine tuner for LH-induced HAS2 expression in ovarian granulosa cells.