he neurotrophins and their receptors are known to regulate the patterns and density of axonal growth of neurons into developing embryonic tissues. By employing in situ hybridization analyses to localize the neurotrophins and their receptors relative to each other during rat embryogenesis, we have observed a developmentally regulated overexpression of some of the neurotrophins in both the motoneurons and the muscle at the time fof motoneuron cell death. The data indicate that BDNF and NT-3 are expressed in the developing motorneurons as well as the muscle these neurons innervate. Furthermore, the levels of the factors and receptors synthesized by the motorneurons and muscle appear to be the highest during stages E16 to E18, the time when the greatest amount of motorneuron cell death is occurring. In addition, we have observed some unusual expression patterns in developing muscle that suggest that some of the neurotrophins and receptors directly influence myogenesis as well as motorneuron innervation. The concomitant neurotrophin-mediated regulation of myogenesis and motoneuron innervation that occurs during embryogenesis has direct implications and applications for the use of the neurotrophins in treating neurodegenerative diseases. The proposed studies are designed to characterize the role of the neurotrophins during developmental events that effect motoneuron innervation of rat embryonic muscle and to apply this information tot he adult animals. The study will consist of three major investigative directions. One group of experiments will be directed toward the quantification of the neurotrophins and their receptors in the motor neurons and muscle relative to the onset and progression of motorneuron cell death during rat embryonic development. These studies will be augmented by experiments defining the effects of various concentrations of competing neurotrophins on the viability of motorneurons in culture. The second group of experiments will be directed toward characterizing the effect of NGF and the factors that bind the trk B receptor on the process of myogenesis. In the third group of experiments, syngeneic fibroblasts and myoblasts overexpressing the neurotrophins or their receptors will be injected into the muscle of adult rats. The transplanted animals well be tested for alterations in the innervation patterns into the muscle and adjacent tissues, the occurrence of motoneuron cell death and the amount of myogenesis. Information from these studies will augment what we know about neurotrophic regulation of motorneurons and give insight into the possible side effects we can expect when neurotrophins are used for treatment of neurodegenerative diseases.
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