MOLECULAR MECHANISMS MEDIATING NERVE MUSCLE INTERACTIONS

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DESCRIPTION (provided by applicant): The molecular mechanisms mediating the development, innervation and stability of sensory axon- mechanoreceptor interactions are very poorly understood, yet they are likely to be important in human neuropathies associated with mechanoreceptor denervation and axon loss. Some human sensory neuropathies primarily affect large diameter sensory axons which preferentially innervate muscle and tendon mechanoreceptors (muscle spindle stretch receptors and Golgi tendon organs) to provide skeletal and muscle position sensation (proprioception) to the central nervous system. During prenatal skeletal muscle development, sensory axons regulate the expression of a specific repertoire of genes in contacted myotubes to mediate stretch receptor morphogenesis and stabilize their innervation. The specific molecular signals that predominate are unknown but identifying them is of considerable interest since proprioception deficits are a common and debilitating aspect of many sensory neuropathies. Without a better understanding of the molecular factors involved in establishing and maintaining innervation to muscle spindle stretch receptors, it will be difficult to formulate rational therapies to slow or reverse proprioceptive axon loss. The signal transduction pathways engaged in myotubes that are contacted by large diameter axons (la- afferents) and the molecular signals involved in maintaining sensory and motor innervation to them are very poorly understood; la-afferents provide instructive signals that transform a subpopulation of myotubes into spindle stretch receptors presumably by engaging gene regulatory networks that are specific for spindle morphogenesis. In previous work, we identified Egr3 as an essential transcriptional regulator of spindle development which is induced in myotubes by la-afferent innervation. This research plan is outlined in three specific aims: (i) to characterize the function of novel Egr3 regulated target genes in stretch receptor morphogenesis and innervation, (ii) to examine whether Egr3 mediated gene expression is sufficient to transform myotubes into intrafusal muscle fibers in the absence of la-afferent morphogenetic signaling and i) to determine whether Egr3 is necessary to fate specify myotubes to an intrafusal muscle fiber lineage. We anticipate that these studies will provide greater understanding of how sensory innervation controls muscle stretch receptor morphogenesis and will better define the role of Egr3 in regulating stretch receptor specific genes that may be involved in stabilizing sensory and motor innervation to them. Muscle and cutaneous thermo- and mechanoreceptors all depend upon sensory innervation for their morphogenesis suggesting that some common molecular mechanisms may be revealed by our studies focusing on nerve- muscle stretch receptor interactions.