Touch sensation is an integral component of our sensory experience, allowing us to perceive and respond to the physical world. Disruptions in touch can profoundly affect the quality of life of patients with severe skin injury and neurological disorders, including peripheral neuropathy. Despite its importance, very little is known about the establishment of touch circuits and the molecular mechanisms that govern mechanosensory neuron morphogenesis and function, due to a prior lack of proper genetic tools. To this end, novel mouse genetic strategies have recently been developed by our laboratory to specifically label the subtypes of cutaneous sensory neurons, known as low-threshold mechanoreceptors (LTMRs). LTMRs convey innocuous mechanosensory information from the skin to the spinal cord dorsal horn and brainstem. With these new genetic tools to label LTMRs early during development, I aim to: 1) characterize the morphogenesis of LTMR peripheral and central projections during development, 2) perform a comprehensive transcriptome analysis for LTMR subtypes during development, and 3) characterize candidate transmembrane proteins identified in the transcriptome analysis in vivo using morphological and functional assays. Using LTMR subtype specific Cre lines, I will visualize individual or groups of LTMR subtypes in mouse hairy skin. This will enable me to characterize their peripheral and central projection morphologies during development, and subsequently perform RNA sequencing for LTMR subtypes to identify uniquely expressed transmembrane proteins. This transcriptome analysis will provide new candidate proteins for mutant analysis, and these genes may regulate LTMR development in many ways, including branching, interaction with their targets, and maintenance. Using a powerful combination of mouse molecular genetic tools, transcriptome analysis, anatomical and electrophysiological assays, I aim to make new discoveries not only about how LTMRs develop, but also about how transmembrane proteins regulate the establishment of LTMR peripheral and central projections. Furthermore, this proposal seeks to provide new potential therapeutic targets for diseases that involve tactile dysfunction such as injury and peripheral neuropathy. While my graduate training provides a solid foundation for studying neural development using genetics, molecular biology and imaging, the proposed RNA sequencing and electrophysiological approaches here represent significant opportunities for personal training and discovery in a highly stimulating and supportive environment.
Alterations of touch sensations can profoundly affect the quality of life of patients with injury and neurological disorders, including peripheral neuropathy. However, the molecular mechanisms governing the establishment and maintenance of touch circuits remain poorly understood. My goal is to identify the molecular regulators of mechanosensory neuron development and maintenance, which will inform new approaches to treat injury and neurological disorders in which the sense of touch is affected.
