Cells in the nervous system interact with several different extracellular matrix proteins that regulate many aspects of their development. Neural development is also regulated by many signaling molecules that are associated with the extracellular matrix. Work over the past decade has shown that integrins mediate many of these interactions. Integrins bind ligands of many classes: extracellular matrix proteins, Ig-family members, disintegrins, a cadherin, proteases and protease inhibitors, and growth factors. Integrins have been shown to regulate many aspects of development including cell proliferation and survival, polarity, differentiation and organogenesis. In the mature nervous system, they have been implicated in the regulation of synaptic function and plasticity. Integrins interact with the cytoskeleton and also regulate signaling through many cytoplasmic pathways including the ERK and Jun kinases, PI-3 kinase, and the cdc-42/rac/rho family of G proteins. The overall aim of this grant is to understand the mechanisms by which integrins and integrin-regulated signaling pathways exert their effects on development of the nervous system. Much of our effort will be focused on an understudied class of integrins, the B8 integrins. We have recently shown that these are essential for normal vascularization of the nervous system. We will try to identify the cellular and molecular pathways that this integrin family regulates to control maturation of the brain vasculature. We will attempt to identify the ligands with which it interacts in the CNS, both inside and outside of the cell. We will determine whether it controls activation of TGF-beta in vivo as has been demonstrated in vitro and will try to determine whether deficits in TGF-B signaling account for the phenotype of the B8 integrin mutant. A foxed B8 integrin allele will be introduced into mice and used to characterize other functions of this integrin in the nervous system. We will also extend our current work on the B1 integrins that, using a foxed allele, we have recently shown are essential for normal formation of the cortex and cerebellum. We will attempt to characterize the signaling pathways controlled by this family of integrins that mediate their effects on normal brain development. In particular, using genetic techniques, we will focus on the role of Focal Adhesion Kinase (FAK) and the signaling pathways controlled by FAK, since FAK is a central mediator of signal transmission by the integrins that have been implicated in cortical development. Among other aims, we will determine whether the essential functions of FAK require its kinase activity or only its function as a scaffold that mediates binding to other signaling proteins.
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