Mechanisms Differentiating Dendrite Development from Axon Development

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DESCRIPTION (provided by applicant): My career goal is to understand the mechanisms of neuronal compartmentalization and how this process contributes to nervous system function and to the pathogenesis of neurological disorders. I will pursue this goal by working in an academic institution as an independent investigator. During my postdoctoral training in the laboratory of Dr. Yuh Nung Jan at UCSF, I have been using Drosophila PNS neurons as a model system to study the mechanisms that differentiate the development of dendrite from axon, two major compartments of a neuron. This training complements my doctoral training in vertebrate neurobiology. I plan to combine the strength of Drosophila (in vivo and superb genetics) and cultured rat hippocampal neurons (well- characterized cell biology) to study neuronal compartmentalization. The objective of this research is to examine the roles of the secretory pathway in differentiating dendrite and axon development. From a genetic screen in Drosophila, we isolated several mutants (dar mutants) with reduced dendritic arbors but normal axons. Dar2, 3, and 6 regulate the secretory pathway, suggesting that this pathway differentiates dendritic and axonal growth. I propose two aims. First, I will determine cell biological mechanisms through which the secretory pathway differentially controls dendritic and axonal growth. New techniques will be developed to complement existing ones to identify such mechanisms. Membrane traffic through the secretory pathway will be monitored in live wild-type and mutant Drosophila embryos/larvae and cultured hippocampal neurons. Second, I will identify and characterize genes that control the differential development of dendrites and axons by regulating key players of the secretory pathway. Dar7 (genetically interacts with dar2 and 3), dar1 (genetic interaction untested), and Trailer Hitch (regulates the secretory pathway) will be studied. Their mammalian homologs will be examined in cultured neurons to determine if the mechanisms are conserved in mammals. This research will provide much-needed information for understanding the causes of neurological disorders characterized by preferential damage to dendrites (e.g., Rett's syndrome) or by defective Golgi function (e.g., amyotrophic lateral sclerosis). Such information will also allow the design of therapeutic approaches.