Identification of proteins that structurally couple epidermal cells to somatosensory neurons

摘要

ABSTRACT Epidermal cells provide the first point of contact for sensory stimuli and are innervated by somatosensory neurons (SSNs) that shape our experience of the world. Both SSNs and epidermal cells are of great clinical relevance; SSNs are mediators of physiological and pathological pain, and some pathological skin conditions are associated with debilitating pain and itch. However, our understanding of roles that epidermal cells play in SSN development and function, particularly nociception, remain limited aside from a few well-studied examples. Characterizing these important intercellular interactions is complicated by the heterogeneity and complexity of vertebrate nervous systems. Here, we propose to use an integrated cross-species approach to identify molecular mediators of an evolutionarily conserved intracellular interaction that involves the wrapping of SSN neurites by epidermal cells. The conservation of this intercellular interaction and the preferential ensheathment of nociceptors compared to other SSNs suggest that these sheaths may play key roles in development and function of nociceptive SSNs. First, we will exploit the advantages of Drosophila neurogenetics to label epidermal sheath- associated proteins for identification by mass-spectroscopy and downstream functional analysis in vivo. Second, we will extend our comparative analysis of invertebrate and vertebrate epidermal sheaths, combining loss-of- function studies in zebrafish and cross-species rescue studies to define conserved functions of a central regulator of sheath maturation. Successful completion of this project will provide insight into the molecular machinery that anatomically couples epidermal cells to nociceptors and contributes to nociceptor development and function. Given the enormous impact of pathological pain on quality of life – chronic pain affects more than one in three Americans – understanding how epidermal cells modulate nociceptive SSN function is of great interest for development of novel therapeutics for pain management.