MOLECULAR MECHANISMS MEDIATING NERVE-MUSCLE INTERACTIONS

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DESCRIPTION (From the Applicant's Abstract): Nerve-muscle interactions play an important role in altering gene expression required for growth and differentiation of muscles. In particular, sensory innervation of skeletal muscle plays a critical role in the genesis of muscle spindles, mechanosensory organs within vertebrate skeletal muscle that provide limb position (proprioceptive) information to the central nervous system. Muscle spindles are innervated by both sensory and motor axons but their genesis is induced specifically by sensory afferents. The tropic effects of sensory afferents are instructive for the transformation of a subpopulation of myotubes to form the complex spindle structure. The molecular mechanisms involved in this complex process are poorly understood. However, we have recently discovered that the zinc-finger transcription factor Egr3 is critically involved in spindle morphogenesis since it is expressed at high levels within forming spindles at a developmental time point that coincides with their induction and since Egr3-deficient mice lack muscle spindles. Egr3 appears to serve as an essential signal transduction molecule expressed in myotubes that have been contacted by sensory axons to form spindles. We have outlined a research program to study the function of Egr3 in mediating the signal transduction mechanisms involved in muscle spindle morphogenesis. Using a variety of in vivo and in vitro molecular techniques we will examine the role of Egr3 in orchestrating gene expression in myotubes during spindle morphogenesis. Motor and sensory innervation to muscle spindles depends upon the neurotrophic factors NT-3 and GDNF which are produced by spindles. We will investigate whether Egr3 regulates these neurotrophins and plays a role in the sensory and motor neuron defects observed in Egr3-deficient mice. Finally, using "gain-of-function" models to overexpress Egr3 both in vivo and in vitro, we will attempt to identify target genes regulated by Egr3 and begin to define the reorganization of gene expression that occurs during spindle morphogenesis. This model system for studying one aspect of nerve-muscle interaction as it relates to the genesis of muscle spindles may be applicable to other mechanosensory organs. It is well appreciated that the genesis of other mechanosensory organs such as Pacinian corpuscles (vibratory sensation), Golgi tendon organs (muscle tension) and Merkel cells (light touch) are also induced by their respective sensory afferent innervation. A more thorough understanding of the reciprocal tropic-trophic interactions between sensory neurons and mechanosensory organs may provide greater insight into the etiopathogenesis of a variety of sensory neuronopathies.