Neurons interact with several different extracellular matrix glycoproteins which help regulate many aspects of their development. Recent work in vertebrates and invertebrates has ascribed a central role in mediating these interactions to a family of heterodimeric receptors named the integrins. This work has shown that integrins have ligands of several classes: secreted ECM glycoproteins and membrane-associated Ig family members, disintegrins, and at least one cadherin. Work has also shown that integrins regulate many aspects of development including cell survival, cell migration, polarity and differentiation, and organogenesis. The overall goal of this project is to understand the roles of integrins in regulating the development of the nervous system. In this grant, we will continue characterization of a novel class of integrins, the beta8 integrins, which we recently showed formed an unsuspected additional set of neuronal receptors for several ECM proteins. We will continue our extensive work on the beta1 integrin family, characterizing their expression patterns, ligands, and essential roles in vivo as assessed by targeted conditional mutation in mice. We will try to understand in more detail how integrin binding to ligand activates intracellular signalling pathways which lead to growth cone motility, assessing the roles of cytoskeletal linker proteins and an integrin-associated tyrosine kinase. We will try to understand the interactions between the NGF and integrin signaling pathways which result in dual regulation of neurite outgrowth by neurotrophins and ECM proteins.
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