Met Signaling in Neural Development and Circuitry Formation

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DESCRIPTION (provided by applicant): This proposed Pathway to Independence award describes a five-year career development plan leading to independent academic research. The applicant is a committed scientist conducting postdoctoral research work in the field of Neurobiology at Vanderbilt for the past four and half years. In July, 2009, he will move with his mentor, Pat Levitt, to the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, where this proposed work will be carried out. The long-term objective of this proposed research aims at understanding the role of the Met receptor tyrosine kinase in neural development and circuitry formation. Met activation by its ligand, hepatocyte growth factor, plays a pleiotropic role in the ontogenesis of multiple organs. In the developing forebrain, Met expression is temporally regulated and peaks during the period of extensive neuronal growth and synapse formation. Recent human genetic studies conducted in our lab and others have identified MET as a risk gene for autism spectrum disorder, a major neurodevelopmental syndrome with disrupted neuronal activity and connectivity. However, the role of Met in synapse function and microcircuit assembly is currently unknown. Three specific aims are proposed: 1) to investigate role of Met signaling in the development and function of the hippocampus. Both morphological and functional alterations in the developing hippocampus will be determined as a result of altered Met signaling (over-expression, knockdown and conditional genetic deletion); 2) to determine molecular mechanisms regulating Met-induced neuronal growth and synaptogenisis in developing hippocampal neurons. In particular, the role of the members of Rho family small GTPases will be studied; 3) to explore potential alterations in the local prefrontal cortex synaptic circuitry resulted from forebrain conditional Met deletion. These studies are important and highly relevant in that they provide mechanistic insights on Met-mediated signaling in forebrain development at molecular, cellular and system levels. Perspectives gained from this study will help the applicant establish research independence and form the scientific basis for achieving his long-term career goals in translational neuroscience research. PUBLIC HEALTH RELEVANCE: Project Narrative Human genetics studies have established MET as a risk gene for autism spectrum disocrders. This proposed study investigates the mechanistic role of Met-mediated signaling in the brain development. Insights gained from this study could offer better understanding of autism pathophysiology and thus be useful for future novel developmental interventions.