Regulation of Neuronal Development by Ubiquitin Pathways

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DESCRIPTION (provided by applicant): The long-term goals of the proposed research are to elucidate the mechanisms that regulate dendrite morphogenesis in the mammalian brain. We recently discovered that the ubiquitin ligase Cdc20-anaphase promoting complex (Cdc20-APC) promotes the generation and elaboration of dendrites in postmitotic mammalian neurons. Genetic knockdown of Cdc20 by RNAi in cerebellar slices and in in vivo in the postnatal rat cerebellum revealed an essential function for Cdc20 in dendrite growth and arborization. Remarkably, Cdc20 is concentrated at the centrosome in neurons, and the centrosomal localization is required for neuronal Cdc20- APC to drive dendrite development. These findings have raised several fundamental questions on how the novel function of Cdc20-APC is regulated in neurons and how Cdc20-APC orchestrates dendrite development. To address these questions, we propose to identify the key domains and posttranslational modifications within Cdc20 that contribute to Cdc20-APC function in dendrite morphogenesis. We will also identify the substrates of neuronal Cdc20-APC that control dendrite growth and elaboration. Finally, based on preliminary evidence, we will characterize the developmental role of a Cdc20-APC in dendrite remodeling and patterning in the cerebellar cortex. The proposed research represents an important set of experiments that will address a major gap in our understanding of the cell-intrinsic mechanisms that underlie neuronal morphogenesis and connectivity. In addition, since abnormalities of dendrite morphology are thought to contribute to the pathogenesis of diverse neurological and psychiatric disorders, including neurodegenerative diseases and mental retardation, the proposed research should provide the foundation for a better understanding of these disorders. PUBLIC HEALTH RELEVANCE: Dendrites are the critical receptive limb of neurons and accordingly the morphology of dendrites is critical for the normal function of neuronal circuits in the brain. We propose to identify the key mechanisms and principles that govern dendrite development. Abnormalities of dendrite morphology may contribute to the pathogenesis of diverse neurological and psychiatric disorders as well as adult neurodegenerative disorders. Therefore, understanding how dendrites are form and shaped is not only essential for a better understanding of brain development but also for insights into a whole host of brain disorders.