Touch sensation, including the perception of form and texture, is essential for our dailylives. Subpopulations of trigeminal and dorsal root ganglion (DRG) neurons are primarysensory neurons mediating this process, and are classified as either rapidly (RA) orslowly adapting (SA) mechanoreceptors. Their molecular identities, unique functions inthe context of form and texture perception, and mechanisms of development are largelyunknown. Recently, I discovered that a small population of DRG neurons that expressthe receptor tyrosine kinase Ret are the elusive RA mechanoreceptors and that Retsignaling is essential for their development. In this application, I propose experiments toelucidate the mechanisms by which Ret and TrkB signaling control survival, peripheralend organ formation, central projections, and physiological properties of RAmechanoreceptors. In addition, I propose to develop new tactile discrimination behaviorassays and a somatosensory neuron specific diphtheria toxin (DTA) mouse line to testthe in vivo functions of RA mechaoreceptors during tactile descrimination.
Specific Aim 1 : To test the hypothesis that Ret and TrkB are redundant for survival ofRA mechanoreceptors and that TrkB functions in RA mechanosensory DRG neuronsautonomously for Meissner corpuscle formation. In this aim, Ret and TrkB doubleknock out mice and TrkB conditional knock out mice will be generated to test myhypothesis.
Specific Aim 2 : To address the mechanism by which Ret signaling directs centralprojections of RA mechanoreceptors. For this purpose, I will visualize the central axonalprojections of individual Ret null RA mechanoreceptors during early development toestablish the nature of the primary axonal projection deficit. In addition, I will identify theendogenous ligand and co-receptor of Ret, and their sources, to establish themechanism of action.
Specific Aim 3 : To determine whether Ret signaling modulates the physiologicalproperties of RA mechanoreceptors. In this aim, physiological properties of RAmechanoreceptors in which Ret is either ablated early during development or acutelyactivated or inhibited in adults will be examined.
Aim 4 : To begin to establish the functional roles of RA mechanoreceptors in vivo. Tostudy the unique functions of various mechanoreceptors, I will develop new behavioralassays to test tactile discrimination in mice. In addition, I will generate a somatosensoryneuron specific conditional DTA mouse line. Together, these new assays and reagentwill enable me to address the role of RA mechanoreceptors and, in the future additionalpopulations of DRG neurons during tactile discrimination.
Texture and form discrimination and the perception of touch are fundamental and important for our daily lives. Our study aims to reveal the development and unique functions of newly identified somatosensory neurons implicated in discriminative touch sensation. Insights from this study will be useful for guiding future strategies at promoting nerve regeneration after spinal cord injury.
