CAREER: Ion Channel Dynamics Driving Proprioceptor Maturation.

All forms of movement require an awareness of where the body and limbs are in space, an internal sense called proprioception. Proprioception requires the activity of specialized sensory neurons, referred to as proprioceptors, that detect changes in muscle movement and force. Proprioceptors transmit this sensory information in the form of electrical signals to the spinal cord. These electrical signals serve as the neural code that guides movement to ensure its accuracy and efficiency and are created by specialized proteins called sodium channels. During early development, as different motor skills, such as walking, are acquired, the proprioceptive sensory system undergoes dynamic changes that enhance movement accuracy and precision, thus making movement more effective. It is unclear, however, how changes in sodium channel function and expression contribute to the maturation of proprioceptor electrical signaling. This knowledge is critical understand how our proprioceptive system develops. Moreover, there are thousands of sodium channel mutations that have been identified in human patients with neurodevelopmental disorders. Notably, these disorders often include severe motor deficits as clinical manifestations; however, these deficits have traditionally been attributed to sodium channel dysfunction in the brain. This work challenges this notion and highlights the critical role of sensory systems for appropriate neurodevelopment. Importantly, this project will also provide educational opportunities to undergraduate researchers from local California State Universities through hands on, paid, summer research experiences, which will be an extension of our successful We Are UC Davis pathways to PhD program. This project advances NSF’s priorities in Biotechnology. This project investigates the cellular and molecular mechanisms that given rise to a mature functional phenotype in mammalian proprioceptors. Proprioceptors are specialized sensory neurons that initiate proprioceptive signaling, which allows for the awareness of body and limbs in space by detecting changes in muscle length and tension. Proprioceptors are highly excitable and rely on three functionally distinct sodium channel (NaV) subtypes to transmit sensory information about muscle movement to the spinal cord. Despite the essential nature of proprioception to all daily activities, how NaVs drive proprioceptor function is poorly understood. The goal of this project is to unravel the complex expression and functional dynamics of each NaV subtype in mammalian proprioceptors across development. This has previously been technically challenging, due to the lack of genetic tools to selectively target proprioceptors, which in turn has hampered progress towards understanding the roles of different ion channels in the proprioceptive sensory system. To overcome this technical barrier, this project will leverage a novel CRISPR/Cas9 intersectional genetic and viral approach developed by the Griffith lab. By combining sensory-neuron specific viral delivery of single-guide RNAs with spatially restricted Cas9 expression, this work will, for the first time, allow for selective targeting of sodium channels in proprioceptors with temporal precision. By combining this approach with behavioral analyses, varied electrophysiological approaches, and quantitative image analysis, the research will analyze the temporal dynamics of sodium channel localization and function in proprioceptors during postnatal development. Collectively, this work will advance knowledge of mammalian proprioception by uncovering the developmental timing of NaV function and localization that drive proprioceptor signaling. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2541818 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT,01003031DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Theanne Griffith | Institution: University of California-Davis, DAVIS, CA | Award Amount: $1,644,245 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2541818 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2541818.html