Somatosensory neurons project peripheral axons to the skin early in development to detect touch stimuli. Although the cutaneous terminals of these axons are often a proportionally small component of the total peripheral axon length, they are critical for function, since they are the sites where touch stimuli are first detected. Cutaneous axon endings are particularly vulnerable to damage by injury, diabetes, and inherited syndromes, notably Charcot-Marie-Tooth diseases. All of these conditions cause debilitating peripheral neuropathies characterized by chronic pain or the inability to sense touch. Characterizing how cutaneous sensory endings are formed, maintained, and respond to injury is thus essential for understanding these conditions and developing effective treatments. We have developed a larval zebrafish model to study the development of somatosensory peripheral axons and the skin cells that they innervate. Because zebrafish larvae are fertilized externally, develop rapidly, and are optically clear, the zebrafish somatosensory system offers unparalleled experimental access to the early stages of skin innervation. By contrast, studying these cutaneous sensory terminals in mammals is challenging, since they develop in utero and their complete three-dimensional structures are difficult to visualize. Most anatomical and molecular features of somatosensory axon territories in the skin are well conserved from fish to mammals, making zebrafish a relevant model for uncovering potential disease mechanisms. Our studies of the past few years have revealed that skin cells play several critical roles in the development, repair and function of somatosensory axon terminals in the skin. The goal of this proposal is to identify and characterize the molecular dialogues between axons and skin cells that regulate the establishment and maintenance of somatosensory axon territories. Using a unique and powerful set of molecular techniques and transgenic tools that we have developed in recent years, we will investigate three questions about the nature of axon/skin interactions during specific stages of somatosensory neuron ontogeny. First, how are sensory axons guided to the skin? Second, once in the skin how do axons become structurally associated with skin cells? And third, how does the skin respond to axon damage and contribute to repair? We will address these questions with a powerful combination of live imaging, embryology and molecular perturbations. Collectively, these studies will provide the first molecular insight into the regulation of several newly discovered functions of skin cells in the development and maintenance of the somatosensory system.
The fine cutaneous endings of touch-sensing neurons are highly vulnerable to damage by inherited neurological diseases (such as Charcot-Marie-Tooth), diabetes, and traumatic injury, all of which cause debilitating neuropathic pain. New findings from our studies of zebrafish larvae indicate that skin cells profoundly influence the development and repair of cutaneous sensory endings, but little is known about the nature of these skin/neuron interactions or how they contribute to disease. Since sensory innervation of skin in zebrafish shares many features with innervation of human skin, our proposed experiments will shed light on diseases that result from defects in these interactions.
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