The vertebrate hindbrain is essential for controlling an array of behaviors, from voluntary movements of thecraniofacial musculature to autonomic functions of the cardiovascular and gastrointestinal systems. Thesebehaviors rely on the precise registration of motor neurons with their peripheral targets along the head andbody's anterior-posterior (AP) axis. This highly ordered relationship originates from a simple embryonic bodyplan in which motor neurons develop within individual rhombomeres and their prospective targets in adjacentbranchial arch tissues. A major cellular contribution to this motor neuron-peripheral target relationship;omes from the neural crest cell, a restricted stem cell population that arises from the dorsal rhombomereand migrates into the surrounding branchial arch tissue. The positional information imposed upon the variedcell types constituting this motor neuron circuit is largely provided by the AP-restricted expression of the Hoxgenes. However, the mechanism that maintains the AP-restricted expression of the Hox genes and theirability to control the differentiation of the neurons derived from the hindbrain and the neural crest cell remainto be defined. In the first aim, we will use a genetic fate map of the rhombomeres to identify the neuronallineages that arise from neural crest cells and their possible regulation by the Hox genes. In the second aim,we will address the role of Hox genes in neuronal differentiation through the use of a conditionalmutagenesis system to disrupt Hox gene function among progenitors and postmitotic motor neurons in theventral neural tube. In the third aim, we will explore a mechanism by which Fgf signaling regulates motorneuron-subtype identity by repressing the activity of the Hox genes in the hindbrain. The latter aim mayreveal a mechanism that establishes the different motor neuron identities along the entire AP axis of thecentral nervous system. An understanding of the molecular and cellular determinants contributing to theformation of the motor neuron-peripheral target circuit may provide therapeutic insight into damaged nervoustissue and diseases associated with motor neurons and nerve conduction.
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