| Apoptosis is essential for the establishment of the complex networks in the vertebrate central nervous system during development. Apoptosis ensures the appropriate size matching between neuron populations and their targets. The surviving neurons rely on signals from multiple sources, such as targets, glia, and afferent connections, to stay viable and functional in the network. Emerging evidence shows that gamma-Protocadherins (PCDH-gammas) also regulate neuronal survival in the vertebrate central nervous system.;PCDH-gammas are vertebrate-specific members of the cadherin superfamily and share a remarkably distinct intracellular domain amongst different isoforms. PCDH-gammas play an essential role in neuronal survival. However, the molecular mechanisms by which PCDH-gammas mediate this function are still not understood. Therefore, the goal of my thesis is to identify the intracellular signaling pathways of PCDH-gammas in regulating neuronal survival.;I conduct a screen to identify PCDH-gamma-interacting partners and focus on one of the candidates, programmed cell death protein 10 (PDCD10). PDCD10 is also known as CCM3, a causative genetic defect for cerebral cavernous malformations (CCM) in humans. I show that PDCD10 interacts with the common cytoplasmic domain of different PCDH-gamma isoforms. In addition, PDCD10 interacts with CCM2, a scaffold protein that also belongs to the CCM family. Using RNAi-mediated knockdown, I demonstrate that the PDCD10/CCM2 scaffold is required for the occurrence of apoptosis upon PCDH-gamma depletion in developing chicken spinal neurons. Moreover, overexpression of either PDCD10 or CCM2 is sufficient to induce neuronal apoptosis.;Using biochemical analysis, I next demonstrate that PCDH-gamma depletion lead to p38/MAPK activation. In addition, RNAi mediated knockdown of either CCM2 or PDCD10 attenuates p38/MAPK activation upon PCDH-gamma depletion. Moreover, inhibition of p38/MAPK activation significantly reduces the apoptotic effect caused by PCDH-gamma depletion. Together, my data support the notion that the PDCD10/CCM2 scaffold promotes apoptosis by activating the p38/MAPK pathway. PCDH-gammas, on the other hand, repress PDCD10/CCM2-induced activation of the p38/MAPK pathway and promote neuronal survival.;In summary, my thesis projects identify a key intracellular signaling pathway downstream of PCDH-gammas. The demonstration of PDCD10/CCM2 function in apoptotic regulatin significantly enhanced our understanding of the molecular mechanisms underlying PCDH-gamma-regulated neuronal survival during development. |
