Coordinated jaw movement results from the complex interaction between jaw, facial, and lingual muscles and requires precise sensory feedback from proprioceptive afferents in jaw muscles. The majority of afferent information from craniofacial musculature is conveyed by the mesencephalic nucleus of the trigeminal system (mesV). Recent studies now suggest that neurotrophins regulate proprioceptive development and recovery following injury. Our recent evidence suggests many of these actions are due to the regulation of axon terminals of proprioceptive neurons, which then radically affects the function of muscle spindles. The long-term objective of this proposal is to characterize cellular and molecular mechanisms involved in interactions between mesV proprioceptive neurons and their targets. The proposed studies will focus on two aspects of afferent-induced sensory endorgan formation: neurotrophin-regulated axon branching axon branching and sensory endorgan morphogenesis. The proposal will utilize two existing NT-3 transgenic animal models and develop two new transgenic models in which target-specific promoters are combined with an inducible promoter to initiate over-expression of NT-3 postnatally, thus bypassing the survival effects of NT-3 in development. With this approach, the biological actions of NT-3 on craniofacial proprioception can be elucidated, and molecules that are directly involved in afferent axon- target interactions can be examined. The first Specific Aim will use transgenic mice to alter the level of NT-3 in postnatal muscle to determine NT-3 affects normal and injured mesV sensory axons. These actions will be correlated with corresponding changes in muscle spindles in jaw-closing and haw-opening muscles.
The aim will then determine how NT-3 affects the terminal arbors of mesV axons by in vivo injection of neurobiotin into single trigeminal neurons. Recently, it was demonstrated that a null mutation in a transcription factor, Egr3, results in abnormal proprioceptive development.
The second Aim will examine the response of the transcription factor Egr3 to abnormal mesV afferent-muscle interactions in NT-3 transgenic mouse models. Finally, this AI will test the hypothesis that Egr3 regulates proprioceptive development by generating transgenic mice that over- express Egr3 in developing skeletal muscle. Results from this study will reveal novel effects of NT-3 on craniofacial sensory neurons, demonstrate how NT-3 may be useful in improving oromotor and facial impairments, and provide important information about molecules involved in the genesis and maturation of trigminal sensory system.
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