Multifunctional roles for doublecortin (DCX)in neural development

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DESCRIPTION (provided by applicant): Wiring the brain is a complex neurodevelopmental process. When it goes wrong, human neurological disorders can arise with deficiencies ranging from mild to severe. Genes associated with such disorders are important avenues for research because they provide an entry point into understanding the molecular mechanisms of both neurodevelopmental processes and diseases. Some neurological disorders are linked genetically to genes ubiquitously expressed in many cell types whereas others are linked to neurally expressed genes. The X-linked gene doublecortin (DCX) is only expressed in neurons and is a major genetic locus for type I lissencephaly, a neurodevelopmental defect causing mental retardation and untractable epilepsy. Unraveling the molecular and cellular functions of DCX, therefore, not only has significance for advancing our understanding of DCX function in development and the disease mechanisms of Lissencephaly, but more generally advances our conceptualization of which proteins in particular are required to make a neuron and wire the brain. This grant thus goes to the heart of understanding cell-type specific mechanisms for making functional neurons and building functional circuits. The molecular and cellular roles of DCX are still incompletely understood. Much work has focused on the microtubule-binding ability of DCX, and the phenotypes associated with DCX mutations are postulated to be due to microtubule-related defects. Patient alleles of DCX are powerful tools to direct our attention to residues in DCX that are important for normal function. Surprisingly, microtubule defects have not been established for most DCX mutations, and it is thus an open question whether all cellular roles of DCX require microtubule binding. Many additional binding partners, such as the cell adhesion molecule neurofascin and clathrin adaptors, have in fact been identified for DCX, but the roles of these other interacting partners are currently not understood. In preliminary experiments, we have identified a novel function of DCX, namely endocytosis of neurofascin. Surprisingly, DCX-mediated endocytosis of neurofascin does not require microtubule binding by DCX in a PC12 assay. We will test the hypothesis that DCX plays roles in multiple cellular processes, including endocytosis, via separable molecular interactions. The objective of this proposal is to uncover the contributions of DCX-mediated endocytosis in neurodevelopment, including migration, axon growth and guidance and dendrite growth.