Abundance of Dual Specificity Phosphatase (DUSP) 1 and DUSP6 mRNA Is Regulated by Hippo Signaling in Bovine Pre-ovulatory Granulosa Cells.

Abstract

Ovulatory disorders are a major cause of infertility in humans as well as economically important species. In physiological conditions, the LH surge induces the expression of epidermal growth factor (EGF)-like ligands that activate the EGR receptor (EGFR) and subsequently the mitogen-activated protein kinase (MAPK) pathway. The magnitude and duration of MAPK phosphorylation are regulated by dual-specificity phosphatases (DUSPs). Besides this well-known cascade, other signaling pathways such as the Hippo pathway modulate the ovulatory cascade and are reported to crosstalk with MAPK signaling. Here, we tested the hypothesis that LH and the Hippo pathway regulate DUSP expression in bovine pre-ovulatory granulosa cells. The abundance of DUSP6 mRNA but not DUSP1 was decreased by LH (P < 0.05). Cells were then pre-treated (1h) with two inhibitors of Hippo signaling, verteporfin (1µM) or peptide-17 (25µM), before exposure for 6h to LH or to EGF. Treatment with verteporfin increased DUSP1 mRNA levels (P < 0.05) in the presence or absence of EGF or LH and treatment with peptide-17 increased DUSP6 and not DUSP1 mRNA abundance. These data indicate a differential regulation of DUSP1 and DUSP6 mRNA by the Hippo pathway in pre-ovulatory granulosa cells, which suggests a complex control of MAPK signaling around ovulation.