Cues in the extracellular microenvironment govern neuronal cell body migration, growth cone motility, and synapse formation by triggering changes in migration speed or direction. The cell surface receptors that interpret these cues engage cytoplasmic partners to transduce signals, but recent work reveals that many receptors also interact laterally with cell surface proteins that can be critical for proper receptor function. Thus, a more sophisticated understanding of cell migration will require a "cell surface interaction map" describing the connectivity of receptors and their cell surface partners. To begin to build such an interaction map, we are studying members of the tetraspanin family of cell surface adaptor proteins. Tetraspanins organize complexes containing integrins (major receptors for extracellular matrix proteins), lg superfamily (lgSF) proteins, growth factor receptors, membrane-bound growth factors, and novel proteins. By targeting tetraspanins, which lie at the center of these complexes, a large number of new cell surface interactions can be uncovered at once. One major focus in the lab is on the tetraspanin protein, TM4SF2, a molecule responsible for one form of X-linked mental retardation. We are trying to unravel the mystery of TM4SF2 involvement in mental retardation by identifying its molecular partners and studying the effect of naturally occurring TM4SF2 mutations on TM4SF2 trafficking, localization, and molecular interactions. A second major focus is on alpha-5 integrin, a receptor for the extracellular matrix protein, fibronectin. We are studying the ability of transgenic alpha-5 integrin to support regenerative neurite outgrowth in CNS neurons. Wild type and modified forms of alpha-5, with different sets of interacting proteins, are being tested for their ability to support neuronal regeneration.

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