Characterizing the Role of Tspan18 in Neural Crest Development

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DESCRIPTION (provided by applicant): The neural crest is a unique, migratory population of stem cells in vertebrate embryos that gives rise to numerous and varied tissues including the peripheral nervous system, craniofacial skeleton, cardiac outflow tract, and melanocytes. The vast number of disorders caused by deregulation of neural crest development, including birth defects such as orofacial clefts and cancers such as neuroblastoma, reflect the diversity of neural crest derivatives. In spite of the key role played by neural crest cells in development and disease, the mechanisms that control the formation of migratory neural crest cells are poorly understood. My preliminary data identify tetraspanin18 (Tspan18) as a novel, critical regulator of neural crest migratory properties. Tetraspanins are transmembrane proteins that organize and regulate cell signaling, motility, and adhesion. The objective of my research is to characterize the role of Tspan18 in neural crest development. I hypothesize that Tspan18 is part of an essential scaffold responsible for organizing signals at the neural crest cell membrane through interactions with other proteins, and that Tspan18 is required for proper neural crest development. Specifically, the proposed research will characterize the role of Tspan18 in neural crest development by (1) determining the requirement for Tspan18 in the neural crest through antisense morpholino oligonucleotide loss-of-function assays, and (2) identifying potential Tspan18 binding partners by affinity purification and mass spectrometry. My rationale for this proposal is that defining the role of Tspan18 in the neural crest will give us insight into the complex web of signals that coordinates early neural crest development, and may provide clues to understanding the progression of disease, such as neuroblastoma. PUBLIC HEALTH RELEVANCE: Neural crest cells are migrating stem cells that form diverse structures in embryos with backbones. When neural crest cell regulation goes awry, a variety of birth defects and cancers results. This research will characterize a novel protein tetraspanin18 that preliminary evidence suggests is required for neural crest development.