Cells in the nervous system interact with different extracellular matrix proteins that regulate their development through interactions mediated by integrins and other receptors, such as dystroglycan and the syndecans. Our recent work has implicated integrins and the integrin-associated proteins focal adhesion kinase (Fak) and integrin-linked kinase (Ilk)in organization of neural epithelial cells and radial glia, deposition of the basal lamina on the surface of the developing CMS,control of radial migration of neocortical neurons, formation of axonal and dendritic branching patterns, and responses to netrin-1. Work of others has indicated that focal adhesion kinase is an important effector through which other axon guidance molecules, such as ephrins and semaphorins, control neuronal development. We will characterize the substrates and signaling pathways through which these kinases regulate basal lamina assembly. We will seek to identify the signaling pathways that control radial migration of neurons in the neocortex that are disrupted by abnormal assembly of the basal lamina on the surface of the neural tube. We will also initiate experiments to identify the downstream effectors of these two protein kinases that are most essential for their functions in controlling neuronal responses to netrin-1 and in controlling axon branching in response to many factors. We will isolate a fak mutant that will permit rapid and specific inhibition of FAK function in defined subsets of neurons and use this mutant to determine whether FAK controls axon branching and synapse development only during embryogenesis or also during axonal and synaptic remodeling in adult animals. We will further characterize the role of p190RhoGEF as a mediator of Fak responses using genetic and cell biological approaches. The results should be important in understanding the molecular deficits that result in type II lissencephaly. They should also contribute to our understanding of the signaling pathways through which an important family of axon guidance molecules controls axon growth, branching and guidance.
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