The neuregulins are a recently discovered family of signaling proteins that are present in high concentrations in a variety of neurons from early developmental times. They have potent and wide-ranging actions on cells that come into contact with the neurons that synthesize them, such as other neurons, muscle cells, and glial cells. These actions include the regulation of neurotransmitter receptors in the post-synaptic cell and the regulation of the survival, differentiation, proliferation, and migration of glial cells. The projects proposed here are concerned with the function of these proteins in the development of the peripheral nervous system in vivo. Specifically the role of neuregulins in the development of the neuromuscular synapse and in the formation of peripheral nerve will be investigated. The function of neuregulins in the regenerative processes that occur in response to injury, such as nerve regeneration and sprouting of motor nerve terminals, will also be examined. Finally, the role of neuregulins in the pathophysiology of diseases such as myesthenia gravis, motor neuron disease, and demyelinating peripheral neuropathy will be explored. A major emphasis will be physiologic and anatomic studies in genetically altered mice--i.e., mice that have been engineered to be deficient in neuregulin expression. The influence of exogenous neuregulins as well as neuregulin inhibitors in normal animals will also be examined. The therapeutic potential of neuregulins will be investigated in animal models of human diseases.
