Gonadotropin Dependent Neuregulin1 Signaling Regulates Luteal Cell Survival

Abstract

The formation of a functional corpus luteum (CL) is an absolute requirement for reproductive success and is induced by the mid-cycle surge of luteinizing hormone (LH). The CL is a transient ovarian endocrine structure that maintains pregnancy in primate during the first trimester and in rodents during the entire pregnancy by producing steroid hormone progesterone (P4). CL growth and differentiation are tightly regulated by both survival and cell death signals, including endocrine (LH), intra-ovarian regulators, and cell-cell interactions. Neuregulin-1 (NRG1) is a member of the epidermal growth factor-like factor family that mediates it’s effect through the erythroblastoma (ErbB) family. However, the detailed mechanisms associated with the interplay of NRG1 and its receptors in CL function is not known. Therefore, we examined the role and action of NRG1 and its receptors in the gonadotropin signaling pathway that impacts CL functions. Immunocolocalization of NRG1 and ErbB2/3 in pregnant rat CL on day 14 and 21 suggest that both NRG1 and ErbB2/3 are differentially expressed in CL. Moreover, both NRG1 and ErbB2/3 are highly expressed in rat CL on day 14 compared to day 21. Furthermore, in vitro studies revealed that rat luteal cells (LCs) treated with exogenous tumor necrosis factor-α (TNFα, an inflammatory cytokine) promoted apoptosis in LCs in a dose and time-dependent manner. However, the effects of TNFα was attenuated in presence of exogenous NRG1. Under these experimental conditions, immunoblot analysis indicated that exogenous TNFα treatment in the presence of NRG1 inhibits apoptosis through increased levels of the anti-apoptotic proteins Bcl2 and Bclxl, and activation of ErbB2-ErbB3-PI3K-Akt signaling pathway. Collectively, these studies provide new insights on the NRG1-mediated anti-apoptotic mechanism in LCs through ErbB3-ErbB2-PI3K-Akt→Bcl/Bcl-xL pathway and may have important clinical implications.Acknowledgements: This study was supported in part by National Institutes of Health Grants 1 SC1 GM130544-01A1, 1SC3GM113751 and G12RR03034. This research was conducted in a facility constructed with support from the Research Facilities Improvement Grant C06RR018386 from the National Institutes of Health National Center for Research Resources.