The LH surge induces ovulation and events associated with this process: oocyte meiotic maturation, cumulus celloocyte complex (COC) expansion, and release of mature (MII arrested) oocytes within the expanded cumulus cell complex matrix. Oocytes and cumulus cells express few if any LH receptors whereas mural granulosa cells exhibit high levels of this gonadotropin receptor. Therefore, in response to the LH surge granulosa cells are presumed to secrete growth factors that mediate the LH receptor activation to the cumulus cells. We determined that not only the EGF receptor (EGFR, ErbB1) but also ErbB2 and ErbB3 were activated in cumulus cells following the LH surge. A possible role for EGFR ligands, amphiregulin (AREG), epiregulin (EREG), and betacellulin (BTC) in the ovulation process was strengthened by recent observations (Park et al. 2004, Shimada et al. 2006). We also identified neuregulin 1 (NRG1) that selectively activates ErbB3 and ErbB2 in mouse periovulatory follicles (Noma et al. 2011). To determine the role of NRG1 in oocyte maturation, we generated a granulosa cell specific Nrg1 knockout mouse (Nrg1flox/flox; Cyp19a1Cre mice; gcNrg1KO, Kawashima et al. 2014). In these mutant mice, the number of oocytes that were ovulated was normal. However, the progression of meiosis in these ovulated gcNrg1KO oocytes was abnormal and was related to the inappropriate activation of PKC and phosphorylation of connexin-43 in cumulus cells of these mutant mice. The abnormal meiosis progression (failure to arrest at MII) decreases successful fertilization and fewer pups were born per litter in gcNrg1KO mice. We conclude that NRG1 is induced by LH in mural granulosa cells and exerts an important regulatory role on oocyte meiotic maturation and competence by the modification of the EGF lignad-EGFR signaling in cumulus cells and preventing premature progression to the MII stage that leads to abnormal fertilization and fertility.
02 Sep 2014 - 04 Sep 2014