This award will support collaborative studies between Dr. Gerald Edelman and his research group at the Neurosciences Institute, Rockefeller University and Dr. Francois Rieger, Unite de Recherche de Biologie et Pathologie Neuromusculaires, Centre National de la Recherche Scientifique, Paris, France. Dr. Edelman, a Nobel Prize winner and eminent researcher in the proposed topic, has collaborated successfully with Dr. Rieger in the past. The neuromuscular system is a complex supracellular structure composed of a number of different cell types: sensory and motor neurons, Schwann cells, muscle cells, fibroblasts, and various support cells. The development, maintenance, and physiological functions of the neuromuscular system depend upon specialized structures, including the neuromuscular junction, the myotendinous junction, and the nodes of Ranvier. In previous research Drs. Edelman and Rieger showed that three glycoproteins involved in cell-cell adhesion are localized to these privileged sites and vary in amount and distribution during development and regeneration of neuromuscular contacts: the neural cell adhesion molecule, N-CAM, the neuron-glia cell adhesion molecule, Ng-CAM, and cytotactin, an extracellular matrix protein. The localization of these molecules was altered in mutant animals with various cellular defects and antibodies to N-CAM blocked the appropriate reinnervation patterns after injury, inhibiting reformation of synapses at old synaptic sites and allowing for extrasynaptic nerve-muscle contacts. The patterns of expression of these molecules correlate with those of other neuromuscular proteins, including acetylcholinesterase, and voltage-dependent calcium channels. During the next phase of collaboration, the investigators will examine the detailed basis for the localized pattern of expression of adhesion molecules and neuromuscular proteins, focusing particularly on cytoskeletal interactions. They will also use cDNA clones specific for muscle forms of N-CAM to transfect cells and produce transgenic animals. These joint experiments would be difficult to accomplish in either laboratory alone. The expertise of Dr. Rieger and his colleagues in electron microscopy, neurophysiology and mutant strains of mice will complement the expertise of Dr. Edelman and his group in the isolation and characterization of cell adhesion molecules, molecular biological techniques, fluorescence microscopy and the production and screening of monoclonal and polyclonal antibodies. These studies should provide new insights into the formation and maintenance of structures crucial to muscle function, as well as to their aberrations in muscle disease and dysfunction.
