c-Kit Receptor Maintains Sensory Axon Innervation of the Skin through Src Family Kinases

Peripheral somatosensory neurons innervate the skin and sense the environment. Whereas many studies focus on initial axon outgrowth and pathfinding, how signaling pathways contribute to maintenance of the established axon arbors and terminals within the skin is largely unknown. This question is particularly relevant to the many types of neuropathies that affect mature neuronal arbors. We show that a receptor tyrosine kinase (RTK), c-Kit, contributes to maintenance, but not initial development, of cutaneous axons in the larval zebrafish before sex determination. Downregulation of Kit signaling rapidly induced retraction of established axon terminals in the skin and a reduction in axonal density. Conversely, misexpression of c-Kit ligand in the skin in larval zebrafish induced increases in local sensory axon density, suggesting an important role for Kit signaling in cutaneous axon maintenance. We found Src family kinases (SFKs) act directly downstream to mediate Kit's role in regulating cutaneous axon density. Our data demonstrate a requirement for skin-to-axon signaling to maintain axonal networks and elucidate novel roles for Kit and SFK signaling in this context. This Kit-SFK signaling axis offers a potential pathway to therapeutically target in sensory neuropathies and to further explore in other neurobiological processes.SIGNIFICANCE STATEMENT The skin is full of small nerve endings that sense different environmental stimuli. How these nerve endings grow and reach a specific area of the skin during development has been the focus of many studies. In contrast, the cellular and molecular mechanisms required to maintain the function and health of these structures is relatively unknown. We discovered that a specific receptor in sensory neurons, c-Kit, is required to maintain the density of nerve endings in the skin. Furthermore, we found that a molecular target of c-Kit, Src family kinases (SFKs), is necessary for this role. Thus, c-Kit/SFK signaling regulates density and maintenance of sensory nerve endings in the skin and may have important roles in neural disease and regeneration.