Molecular regulation of neural stem cell apoptosis

Neural precursor cells (NPCs) consist of multipotent neural stem cells and mitotically active lineage-restricted neural progenitor cells. NPCs can be found in the embryonic ventricular zone, the external granule cell layer of the postnatal cerebellum, and the subgranular and subventricular zones of the adult brain. NPCs in these regions are sensitive to a number of apoptotic insults. The regulation of apoptosis in NPCs is primarily accomplished by members of the Bcl-2 and caspase protein families. The Bcl-2 family of proteins consists of both pro- and anti-apoptotic members and contains characteristic Bcl-2 homology (BH) domains. Pro-apoptotic Bcl-2 family members include the BH3-domain only proteins, which are thought to respond to a diverse array of apoptotic stimuli and lead to the activation of the intrinsic apoptotic pathway. Caspases are cysteine proteases and are necessary for the initiation and execution of intracellular cleavage events that are required for a cell to die an apoptosis death. In addition to the Bcl-2 family and Caspases, the tumor suppressor protein p53 is required for NPC death following several apoptotic stimuli. p53 is the most frequently mutated gene found in human cancers. p53 responds to cellular stress by activating both cell cycle arrest and apoptosis. A large number of target genes are regulated by p53 via trans-activation and trans-repression. Furthermore, recent evidence suggests that p53 may have pro-apoptotic activity outside of the nucleus that is not associated with gene transcription. Little is known about how p53 coordinates the apoptotic response in NPCs. In this dissertation, the role of cell death in NPC function and dysfunction is introduced. Then, current evidence for Bcl-2 family regulation of apoptosis in the nervous system, in both normal and pathological conditions, is presented. Next, Noxa and Puma, two BH3-domain only molecules and p53 target genes, are shown to regulate NPC apoptosis in response to genotoxic injury. Finally, p53 is shown to have both transcription-dependent and transcription-independent pro-apoptotic functions in NPCs. Collectively, the work presented in this dissertation advances our understanding of the molecular pathways regulating apoptosis in NPCs.