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

Abstract

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.