UC Riverside

Proper nervous system function requires neurons to make synaptic connections with the appropriate partners, ensuring the formation of precise circuits. Even transient developmental delays in cell migration, lamination, neurite outgrowth, axon guidance, synapse assembly or refinement might have lasting consequences, as manifested in a wide range of neurodevelopmental disorders. Underscoring each of these cellular processes is the requirement of newborn neurons and glia to dynamically alter their morphology in response to extracellular cues. Failure to appropriately remodel the cytoskeleton during any of the above processes may result in changes to nervous system architecture, circuit organization and physiology, and consequently behavioral or cognitive function. Therefore, to understand how neurons organize themselves into functional circuits, it is imperative to understand how neural cells remodel their cytoskeleton in response to instructive and permissive cues from the environment. Many neuronal guidance cues that regulate circuit assembly have been functionally characterized, yet little is known regarding the intracellular effectors that these ligand-receptor pairs utilize to modulate cellular adhesion and cytoskeletal remodeling during neuronal guidance events. Here, I present the combined studies of three intracellular effectors at the crossroads of adhesion and guidance signaling. In chapter 1, I provide genetic evidence the Crk-Associated Substrate (Cas) family of adaptor proteins are required for the proper fasciculation of several forebrain tracts. In chapter 2, I present the design of a novel luminescent-based, genetically-encoded tool for live cell analysis and quantification of adhesion signaling events upstream of Focal Adhesion Kinase. In chapter 3, I provide genetic evidence the RacGAP β-chimaerin is required for cerebellar lamination. Collectively, these studies provide novel insights into the cytoplasmic effectors essential for the regulation of cell adhesion and cytoskeletal remodeling during circuit building events.