ERK mediated regulation of RbAp46/48 during female germ cell development

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PROJECT SUMMARY ERK (Extracellular signal Regulated Kinase) signaling is critical for female fertility and normal embryonic morphogenesis. Two key events that ERK signaling regulates to control female fertility are (a) progression of female meiosis I and (b) resumption of oocyte meiosis after prolonged arrest (also called oocyte meiotic maturation). Stereotypical execution of meiosis I requires that homologous chromosomes pair, align, form physical connections, exchange genetic information and segregate homologs into gametes. Mis-regulation of any of these steps results in failures in chromosome segregation causing severe developmental disorders, e.g., the Down’s syndrome. We find that loss of erk signaling results in failure of chromosomes to maintain synapsis causing embryonic lethality. In addition to meiosis I progression, ERK activation is essential for oocyte development and resumption after prolonged arrest in meiosis I. Oocytes arrest in meiosis I for decades in humans, an event that is critical for reproductive fitness of the species. Meiosis I is then resumed as the oocyte matures and the process of oocyte meiotic resumption or maturation is coordinated through hormonal signaling and ERK activation. Failure of oocytes to either undergo arrest or fail in meiotic maturation results in female sterility or birth defects. Inappropriate ERK signaling results in defects in oocyte meiotic maturation causing sterility or birth defects. Determining the proteins that ERK phosphorylates and regulates to mediate these two events that control female fertility and embryonic morphogenesis will guide not only our understanding of female reproduction but also provide effective measures to modulate the pathway for interventions. We identified two proteins RbAp46 and RbAp48 as ERK substrates that regulate chromosome dynamics during meiosis I and oocyte meiotic maturation respectively. RbAp46/RbAp48 are paralogous proteins that function as histone chaperones in the Polycomb Repressive Complex 2 (PRC2) and Nucelosome Remodeling Complex (NuRD) in worms and mammals to regulate epigenetic marks and transcriptional silencing, this is the first description of (i) their regulation by ERK signaling and (ii) their function in regulating female meiosis I and oocyte maturation. The goal of this proposal is to understand the genetic and molecular basis of these functions.