How distinct cell fates are generated from initially homogeneous cell populations is a fundamental question in developmental neurobiology. The neural crest is one such cell population that is capable of producing an incredible array of derivatives. Cells as different in function and form as the pigment cells in the skin or the neurons and glia of the peripheral nervous system are all derived from neural crest. Studies to understand the specification of a specific cell type, dorsal root ganglion (DRG) sensory neurons, are proposed. The transcription factor Ngn1 is critical for DRG specification. We have developed a transgenic line where DRG precursors are marked by GFP expression regulated by ngnl control elements. We propose to use this line to understand the regulatory pathways involved in DRG specification. We will examine the roles of the Notch signaling pathway in regulating sensory neuron cell number. We will also follow the addition of new DRG neurons from latent precursors long after neural crest formation has ceased. In addition, a forward genetic screen has identified three mutations that alter DRG development. We propose to characterize the locus of mutation action and identify the underlying molecular lesions. Finally, we propose a new screen to identify additional mutations. Understanding sensory neuron development may eventually help in the design of therapies for improving function in patients affected with neurodegenerative diseases, diabetes-related sensory neuropathy, and pain disorders. ? ? ?
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