Investigating The Role Of The Mapk Proteins Erk1 And Erk2 On Mammalian Gametogenesis
Gametogenesis is one of the most important biological processes in the life of an organism because it results in the production of gametes, haploid cells that pass on the organism's genetic material to its offspring. However, it a very complicated, intricate process that demands a very high level of regulation. This regulation is to ensure error free meiotic and post-meiotic divisions resulting in a haploid gamete. Errors during the meiotic process can result in defective embryos or fetal demise. Among mammals, humans exhibit a very high rate of gamete defects (~25%) leading to high rates of early embryo loss. Stage-specific cell signaling cascades such as the MAPK pathway regulate meiosis and germ-cell development. In addition to this, MAPKs specifically ERKs, are thought to be involved in cellular division, cytoskeletal reorganization and segregation of genetic material. So far pharmacological approaches have been used to study the action of ERKs in oocytes in vitro using inhibitors of the ERK pathway. However, these are not truly reflective of the physiological environment of the ovary. Hence, in order to better understand the mechanism of action of ERKs on oocyte division, I have generated an Erk2 conditional deletion system driven by an oocyte specific Cre on an Erk1 null background. I hypothesized that deregulation of the MAPK pathway in oocytes will produce drastic changes in the cytokinesis and in chromosome segregation. Mutant females were found to be infertile, with gross chromosome misalignment on metaphase spindles in oocytes, and severe early embryonic loss. This phenotype was accompanied by loss of phosphorylation of several downstream targets such as MSK1 and histone H3. Several possible new targets have also been identified in this study by comparing phosphrylation profiles of oocytes from various genotypes. Our results demonstrate that ERK activity specifically within the oocyte is essential for meiotic resumption and for normal pre-implantation development.
ERK; Oocyte; Meiosis
Johnson, Patricia A; Coonrod, Scott A.; Southard, Teresa L; Roberson, Mark Stephen
Ph.D. of Physiology
Doctor of Philosophy
dissertation or thesis