Identification, Development and Function of Rapidly Adapting Mechanoreceptors

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Touch sensation, including the perception of form and texture, is essential for our daily lives. Subpopulations of trigeminal and dorsal root ganglion (DRG) neurons are primary sensory neurons mediating this process, and are classified as either rapidly (RA) or slowly adapting (SA) mechanoreceptors. Their molecular identities, unique functions in the context of form and texture perception, and mechanisms of development are largely unknown. Recently, I discovered that a small population of DRG neurons that express the receptor tyrosine kinase Ret are the elusive RA mechanoreceptors and that Ret signaling is essential for their development. In this application, I propose experiments to elucidate the mechanisms by which Ret and TrkB signaling control survival, peripheral end organ formation, central projections, and physiological properties of RA mechanoreceptors. In addition, I propose to develop new tactile discrimination behavior assays and a somatosensory neuron specific diphtheria toxin (DTA) mouse line to test the in vivo functions of RA mechaoreceptors during tactile descrimination. Specific Aim 1: To test the hypothesis that Ret and TrkB are redundant for survival of RA mechanoreceptors and that TrkB functions in RA mechanosensory DRG neurons autonomously for Meissner corpuscle formation. In this aim, Ret and TrkB double knock out mice and TrkB conditional knock out mice will be generated to test my hypothesis. Specific Aim 2: To address the mechanism by which Ret signaling directs central projections of RA mechanoreceptors. For this purpose, I will visualize the central axonal projections of individual Ret null RA mechanoreceptors during early development to establish the nature of the primary axonal projection deficit. In addition, I will identify the endogenous ligand and co-receptor of Ret, and their sources, to establish the mechanism of action. Specific Aim 3: To determine whether Ret signaling modulates the physiological properties of RA mechanoreceptors. In this aim, physiological properties of RA mechanoreceptors in which Ret is either ablated early during development or acutely activated or inhibited in adults will be examined. Aim 4: To begin to establish the functional roles of RA mechanoreceptors in vivo. To study the unique functions of various mechanoreceptors, I will develop new behavioral assays to test tactile discrimination in mice. In addition, I will generate a somatosensory neuron specific conditional DTA mouse line. Together, these new assays and reagent will enable me to address the role of RA mechanoreceptors and, in the future additional populations of DRG neurons during tactile discrimination.