The peripheral nervous system (PNS) is essential for life. Our ability to autonomously respond to alterations in oxygen levels, CO2, blood pressure, and detection of noxious stimuli that could harm the organism, are all critical functions mediated by the PNS. When the development of these systems go awry, sensory and/or autonomic neuropathies result including the recessive genetic disease, Familial Dysautonomia (FD), in which neither the sensory nor the autonomic nervous systems develop correctly. Most of the PNS derives from a quixotic population of stem-like cells, the neural crest. These cells delaminate from the neural tube, and migrate along stereotyped trajectories throughout the embryo to ultimately give rise to the majority of derivatives within the PNS. Although over the past 10 years, many of the molecular mechanisms that mediate sensory neuron development have been identified our understanding of the cellular mechanisms that orchestrate the behaviors of NCCs as they give rise to specific derivatives is sparse. However, with the revolution in live imaging technologies and fluorescent protein variant reagents, combined with the ease of conducting in vivo gain and loss function perturbations in the avian embryo, it is now possible to image in real time the migration and differentiation of neural crest cells while simultaneously conducting molecular perturbations. We will combine these powerful technologies in this proposal to investigate whether distinct subpopulations of neural crest cells give rise to subtype-specific classes of sensory neurons in the dorsal root ganglia. To this end, we will use photoactivatable GFP variants, gene-specific reporter constructs, and retroviruses to track neural crest cells that emigrate from spatially discrete regions of the neural tube, over the three temporally distinct waves of emigration, and trace their lineage as they give rise to subtypes of progenitor cells and sensory neurons. Furthermore we will extend what we learn from studying normal sensory neuron development to investigate the underlying molecular and cellular mechanisms that go awry to result in FD by analyzing sensory neuron development in both mice and chick in which the gene responsible for the FD disease is deleted (mouse) or knocked-down (chick).
Our work is focused on understanding how pain-sensing neurons are born and mature. These neurons are essential for life as protection against noxious stimuli that could harm the organism. Achievement of the aims of our proposal will identify cellular and molecular mechanisms that can be applied to the treatment of both developmental and degenerative peripheral neuropathies including Familial dysautonomia and diabetic peripheral neuropathy.
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