The roles of Mcl-1 and Bcl-x in central nervous system development

Changes in survival signaling through the stages of developmental neurogenesis are poorly understood. This thesis examined the role of anti-apoptotic Bcl-2 proteins, Mcl-1 and Bcl-x in promoting survival as cells progress through neurogenesis using Nestin-mediated conditional deletion of mcl-1, bcl-x or both in the mouse embryonic central nervous system. My results show Mcl-1 is required earlier in development in precursor populations, while Bcl-x is required for the post-mitotic cells. However, loss of a single bcl-x allele exasperated apoptotic death in the mcl-1 knockout revealing a novel role for Bcl-x in precursor cells. Furthermore, the double knockout exhibited a more severe phenotype with complete loss of the central nervous system. To determine ho Mcl-1 and Bcl-x promote cell survival, qPCR and in situ hybridization were used to examine the expression profiles of pro-apoptotic bcl-2 genes. This study demonstrates the distinct and overlapping requirements of Mcl-1 and bcl-x through murine neural development