This proposal has two overall, interrelated goals. The first is to deepen our understanding of how synapses are formed, shaped, maintained and eliminated. The second is to elucidate how the integrity of the muscle fiber membrane is maintained, with particular regard to muscular dystrophy. Agrin secreted from the nerve terminal induces the formation of nerve-muscle synapses. The agrin signaling receptor MuSK is essential for this induction. However, agrin does not bind MuSK directly and the mechanisms of MuSK activation and localization are unresolved. In the previous funding period we discovered a novel component of Torpedo electric organ postsynaptic membranes, biglycan. Biochemical studies show that this small leucine-rich repeat proteoglycan (SLRP) binds via distinct domains to a a-dystroglycan, the ectodomain of MuSK and to a-and g- sarcoglycan. Both biglycan and its homolog decorin induce MuSK tyrosine phosphorylation when added to cultured myotubes. Moreover, agrin-induced AChR clustering is greatly reduced on myotubes from biglycan null (biglycan-10) mice. Finally, serum creatine kinase levels are markedly elevated in biglycan-10 mice. Together, these observations point to an important role for biglycan and/or decorin in postsynaptic differentiation, and for biglycan in maintaining the integrity of the muscle cell plasma membrane. In the present proposal we will take a combined molecular, biochemical, cell biological, and genetic approach to elucidate the role of biglycan and decorin in synaptic differentiation and in maintaining muscle cell integrity.
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