Title: Does inappropriate expression of the Trk B non-catalytic receptor disrupt peripheral innervation during development? The trk B neurotrophin receptor has three isoforms, one of which is a tyrosine specific kinase receptor that binds the neurotrophins BDNF and NT-4. The activation of the catalytic and receptor generates signal that stimulate growth and viability of certain types of neurons. The other two isoforms of the trk B receptor are non-catalytic. They have extracellular domains that are identical to that of the catalytic isoform but have short intracellular domains that lack the tyrosine-specific kinase activity. Data will be presented that show the trk B non-catalytic isoforms are expressed by developing non-neural tissues that surround target tissues innervated by neurons. The patterns of expression indicate that the receptor may be serving as a molecular buffer that regulates the concentration of neurotrophins in the target tissue by binding and sequestering factor that diffuses away from intended innervation sites. The purpose of the proposed studies is to test the hypothesis that the non- catalytic trk B receptors can bind and sequester factor and thereby influence the innervation patterns of a developing target tissue. The experiments are functional in nature and involve both in vitro and in vivo assays. The in vivo experiments will focus on the developing muscle for three reasons. First, the preliminary data indicate that the trk B receptor may have a function in the development of the innervation patterns of the muscle. That role is not fully defined. The studies proposed below will clarify at least one of the functional roles of the non-catalytic trk B receptors. Second, the studies will contribute new insight into what the ligands for trk B may be doing to promote motor neuron growth and/or synaptogenesis in muscle. Third, the transgenic animals generated from the study will help clarify the role of the neurotrophins in the neuromuscular system and may present a phenotype that can be exploited as a model of neuromuscular degeneration. By elucidating the functions of the non-catalytic receptor in regulating innervation and/or synaptogenesis of motor neurons onto muscle, it will be possible to determine the best possible use for the neurotrophins in treatment of neuromuscular degenerative diseases and/or motor injuries.
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