Role of exosomes in the coordinated migration of neural crest cells and placodes and ethanol-induced teratogenesis

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Fetal Alcohol Spectrum Disorders (FASD) is the leading known cause of mental retardation. Growing evidence suggests a major contribution of the disruption of neural crest cell (NCC) and placode (PC) migration to ethanol- induced craniofacial and cranial nerve defects. However, there is a fundamental gap in understanding how ethanol disrupts the coordinated migration of NCCs and PCs in embryos. Exosomes have recently emerged as an important mode of intercellular communication. Exosomes carry and transfer a variety of active molecules, including microRNAs to and act on local and distant recipient cells, and affect their functions. We have recently demonstrated that exosomes derived from human NCCs mediated ethanol-induced repression of SDF1/CXCR4 signaling and subsequently disrupted the coordinated migration of NCCs and PCs and that disruption of NCC and PC migration contributes to ethanol-induced craniofacial and cranial nerve defects in zebrafish embryos. The overall objective of this proposal is to elucidate the mechanisms by which exosomes mediate ethanol- induced repression of SDF1/CXCR4 signaling, disruption of the coordinated migration of NCCs and PCs, and craniofacial and cranial nerve defects, and to establish plant-derived exosome-like nanoparticles as a feasible strategy for the prevention of FASD. The central hypothesis of this project is that ethanol disrupts the coordinated migration of NCCs and PCs through NCC-derived exosome-mediated repression of SDF1/CXCR4 signaling, subsequently leading to craniofacial and cranial nerve defects, and that modulation of SDF1/CXCR4 signaling by grape exosome-like nanoparticles (GELNs) or GELNs loaded with miRNA modulators can prevent ethanol- induced teratogenesis. To test our hypothesis, the following specific aims will be addressed: Aim 1: To characterize the role of exosomes in ethanol-induced disruption of the coordinated migration of NCCs and PCs in vitro and in zebrafish embryos. Aim 2: To elucidate the mechanisms by which NCC-derived exosomes mediate ethanol-induced repression of SDF1/CXCR4 signaling and disruption of the coordinated migration of NCCs and PCs. Aim 3: To test the hypothesis that exosomes derived from NCCs mediate ethanol-induced craniofacial and cranial nerve defects and that modulation of SDF1/CXCR4 signaling by GELNs or GELNs loaded with miRNA modulators represents a novel therapeutic strategy for preventing FASD. The proposed work is innovative, because this is the first study attempting to prevent FASD through the newly recognized role of exosomes in intercellular communication and the actions of SDF1/CXCR4 signaling in modulating the coordinated migration of NCCs and PCs. It also represents the first attempt to prevent FASD using edible plant-derived exosome-like nanoparticles. The proposed research is expected to characterize a novel, exosome-mediated intercellular interaction between NCCs and PCs during ethanol-induced teratogenesis. Such results will be significant, because the insights gained from this study will help in elucidating the mechanisms underlying FASD and yield exosome-based strategies for the prevention of FASD.