MOLECULAR REGULATION OF NOCICEPTIVE NEURON DEVELOPMENT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the nervous system, pain is sensed by nociceptive neurons that reside in the dorsal root ganglia (DRG) that flank the spinal cord. These neurons derive from migrating neural crest cells and are absent in mice deficient in neurogenin1 (ngn1), but little else is known about the molecular mechanisms that regulate the development of these neurons. The loss of nociceptors in ngn1 null animals provides an important entry point into the characterization of factors that regulate nociceptive neuron development. Since ngn1 is required for their formation, identification of factors that regulate ngn1 expression in nociceptive neuron progenitors will lead to a better understanding of the early regulation of this lineage. Also, identification of effectors downstream of ngn1 will lead to a better understanding of nociceptive neuron differentiation. Potential candidates that may regulate nociceptive neuron development are the bone morphogenetic proteins (BMPs). BMP ligands, as well as type I and type II BMP receptors, are expressed in developing DRGs, and cell culture experiments have shown that BMPs promote the expression of a neuropeptide known to be expressed by nociceptive neurons. To identify factors involved in the regulation of nociceptive neuron development and to test the hypothesis that endogenously expressed BMPs regulate the differentiation of nociceptive neurons, the following specific aims will be pursued: 1) DRG specific regulatory elements in the ngn1 promoter will be identified as a way to identify upstream regulatory factors; 2) downstream effectors of the ngn1 gene will be identified by comparing gene expression in wild type and ngn1 null DRGs by microarray analysis; and 3) the role of BMPs in nociceptive neuron development will be tested by up- and downregulating BMP signaling in developing nociceptive neurons in vivo. This study will contribute to our understanding of neuronal growth and differentiation in the developing nervous system and should provide insights into regeneration following disease or injury, and potentially for alleviating chronic pain.