Role of Cas adaptor proteins during cortical axon pathfinding

SUMMARY Establishment of proper connections in the developing brain is essential for perception, language, thought, consciousness, learning and memory. Disruption of any of the developmental events that participate in circuit formation can result in a range of neurodevelopmental disorders. Interestingly, signaling by the same guidance cues is used and re-used at different developmental stages to instruct cell migration, neurite guidance, lamination, synapse assembly and pruning. During these developmental events neurons encounter multiple signals at the same time. Does a ligand-receptor pair engage the same downstream signaling effectors regardless of the particular developmental process? How are multiple signaling cues integrated within the cell? To begin to answer these fundamental questions we will study the Cas (Crk associated substrate) family of cytosolic signaling adaptor proteins. Cas proteins are known to signal downstream of both integrins and axon guidance cues, and are differentially phosphorylated by these pathways. This makes the study of Cas protein function a unique opportunity to understand how adhesive and instructive pathways are interpreted and coordinated inside the neuron during embryonic development. Newly developed tools will probe deeply into the functional role for Cas proteins during cortical axon guidance and fasciculation. Given the potential for Cas proteins to act as a nexus where instructive and permissive signaling pathways converge to regulate cell adhesion, these studies will likely increase our understanding of circuit development by: 1) exploring a newly discovered requirement for Cas proteins during cortical development; 2) providing new insight into the poorly understood crosstalk between adhesion to the substrate and guidance cue signaling during axon pathfinding in vivo; 3) contributing to our understanding of how disrupted connectivity impacts cortical processing; 4) providing a platform to assess cortical circuit features underlying normal local and long-range neocortical communication.