The role of Neuregulin-1 (NRG1) in corpus luteum (CL) physiology 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 the production of steroid hormone progesterone (P4). CL defects contribute to decreasing P4 production and subsequent inability to support a developing fetus and reproductive failures. CL growth and differentiation are tightly regulated by both survival and cell death signals, including endocrine (LH), intra-ovarian regulators and cell-cell interactions. The interplay between the LH, P4 and inflammatory markers have been well established in human and animal models. For maintaining pregnancy, luteal establishment and development of highly vascularized CL upon fertilization, a plethora of pro-inflammatory and pro- apoptotic factors are needed for tissue remodeling of the ovulated follicle. Whereas, to protect ovulated follicle and its surrounding cells/tissues for the formation of a functional CL requires a plethora of pro-survival and anti- inflammatory factors to fine-tune and counterbalance mechanism against pro-apoptotic and pro-inflammatory factors to create a favorable environment to maintain CL differentiated state and stage. Previously our lab has demonstrated that NRG1, a member of epidermal growth factor (EGF) family, is gonadotropin (follicle stimulating hormone, FSH and LH) dependent differentially regulated in granulosa cells (GCs) and theca cells, and secreted in the ovarian follicular fluid (FF) as a cellular survival factor. Other labs have demonstrated that NRG1 enhances amphiregulin (AREG)-induced P4 production in GCs, and exerts an important regulatory role in oocyte meiotic maturation, and prevent premature progression to the metaphase II (MII) stage that leads to abnormal fertilization and fertility. Our preliminary studies detected LH dependent expression of NRG1 in rat luteal cells (LCs) and CL. Furthermore, our preliminary studies also provided novel evidence that NRG1 plays an important role in LCs survival and inhibition of inflammatory cytokines and chemokine secretion, and suggest a possible role in LCs maturation and differentiation, and, may act through an autocrine and/or paracrine mechanism. The anti-inflammatory and pro-survival functions of NRG1 and its underlying mechanism of action in LCs and CL functions are yet to be defined. Our long-term goal is to understand the physiological role of NRG1 on CL differentiation through obtaining insights into its anti-inflammatory and pro-survival effect in mechanistic detail. Thus, the central hypothesis to be tested in this proposal is that NRG1 is a critical cellular mediator of LH stimulation of LCs, which supports CL function.
An understanding of the novel functions of NRG1 and its underlying molecular mechanism in luteal cells (LCs) survival and anti-inflammatory role have profound implications in the field of fertility (contraception or infertility), and as molecular diagnostic and extended therapeutic tools (population-based screenings).