Grant: Operating Grant

Neurons have complex architectures that change with time. Most neurons initially produce extensive and elaborate processes that are subsequently pruned so that only those that are used to mediate neuron-neuron communication, and thus form part of a neuronal network, are retained. After injury, damaged neuronal processes can be removed, through activation of these same pruning mechanisms. My lab studies the intracellular cascades that regulate cellular life and death decisions. Our cells have the capacity to activate an intrinsic suicide program and this plays a crucial role in sculpting tissues during development and in maintaining homeostasis in the adult. This suicide program can have dire consequences if it is not tightly controlled and therefore cells use a variety of overlapping mechanisms to regulate this process. Recent findings have shown that the core cellular machinery that drives cell suicide is also used to selectively prune processes in the nervous system. Thus, the same pathways that drive cellular lethality can be used to regulate sub-lethal events in the nervous system. The goal of this proposal is to understand precisely how this program is controlled - we want to understand how the neuron activates the program that drives neuronal pruning and, at the same time, restrains it so it sculpts the neuron but does not kill it. This research program will identify fundamental conserved mechanisms that allow neurons to remove some of their processes while retaining others, while keeping the neuron itself alive. This work may have translational implications since emerging evidence indicates that inappropriate re-activation of the sculpting program is an early pathogenic event in neurodegenerative disease. Gaining new insights into the fundamental signaling and regulatory mechanisms that regulate neurite destruction may reveal therapeutic opportunities to slow neurodegenerative disorders.