The extracellular matrix has long been recognized as a scaffold for developing and regenerating tissues. Recently the matrix has been shown to have more specific effects on cellular differentiation. In the case of regenerating muscle, studies demonstrate that molecules associated with the synaptic portion of the matrix direct the accumulation of specific components on myofibers and nerve terminals. Although the functional components of nerve and muscle have been identified, little is known about how they are brought together into the orderly arrangement necessary for synaptic transmission. Dr. Nitkin will examine the role of extracellular matrix factors in the development of synaptic structure at the neuromuscular junction. During regeneration, factors associated with the matrix direct the differentiation of both pre- and postsynaptic elements. Dr. Nitkin and his colleagues will focus on agrin, a matrix molecule that induces discrete synapse-like patches on myotubes grown in culture. They will use cellular and molecular approaches in culture to examine the following aspects of synapse formation: (1) What is the biochemical nature of the active molecule? (2) How is agrin integrated into the extracellular matrix at the neuromuscular junction? (3) How does agrin interact with myotubes to bring about synaptic differentiation? The results of these experiments will increase our understanding of the mechanisms of synapric organization, and may eventually contribute to the design of clinical strategies for facilitating regeneration of nervous tissue.
