REGULATION OF NEURAL CREST CELL MIGRATION BY SDF1-CXCR4 SIGNALING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We plan to study the role of signaling from the chemokine stromal cell-derived factor-1 (SDF-1) through its specific receptor CXCR4 in the migration of trunk neural crest cells to the dorsal root ganglia (DRG). The study will investigate the following hypotheses: [1] the chemokine guidance receptor CXCR4 is expressed in neural crest cells during migration into the DRG in distinct spatio-temporal patterns, while its activating ligand, SDF-1, is expressed along the pathways of neural crest migration; [2] loss of function of SDF-1/CXCR signaling during embryogenesis results in altered migration of neural crest cells into the developing DRG; [3] expression of the CXCR4 chemokine receptor and its activating ligand, SDF-1, is regulated by the TGF¿ superfamily members BMP4 and TGF¿1, respectively; [4] the downstream effects of SDF-1/CXCR4 signaling which govern migration of the neural crest cells to the DRG during embryogenesis, are mediated by the phosphatidyl-inositide-3 phosphorylation signal transduction pathway. The neural crest is a progenitor cell population contributing to a multitude of cell and tissue types, including the DRG and sensory nervous system. ¿ Signaling of the chemokine SDF-1 through its specific receptor, CXCR4 is required for the migration of many stem cell and progenitor cell populations from their respective sites of emergence to the regions where they will differentiate into complex tissues and organs. Deletion of the entire CXCR4 or SDF-1 gene in mice results in perinatal lethality at approximately gestational day 18.5 due to cerebellar, cardiac and hematopoietic defects. The global objective of this research program is to determine whether the chemokine SDF-1 is required for migration of trunk neural crest cells to the DRG during embryogenesis and whether the disruption of SDF-1 signaling to its specific receptor, CXCR4, results in altered neural crest migration and/or abnormal formation of the DRG. The research program will also investigate regulation of SDF-1 and CXCR4 expression by TGF¿1 and BMP4 in the embryo during the time of neural crest cell emigration from the dorsal aspect of the neural tube and neural crest cell migration to the dorsal root ganglia. BMP and TGF¿ are two factors that play important roles in embryonic development, and regulate SDF-1 and CXCR4 expression in a variety of adult cell types in culture. Finally, the research program will investigate whether the downstream effects of SDF-1/CXCR4 signaling during embryonic neural crest cell migration to the DRG are mediated by the phosphatidyl-inositide-3 phosphorylation signal transduction pathway. Abnormal development of the peripheral nervous system in both mice and zebrafish following functional inactivation of the SDF-1 - CXCR4 chemokine signaling axis suggests a role of CXCR4/SDF-1 in migration of trunk neural crest cells to the forming DRG during embryogenesis. However, virtually no mechanistic information is available at present. In view of the deleterious physiological defects caused by aberrant DRG and sensory neuron development in conditions such as Waardenburg-Hirschsprung Disease and WHIM, investigations of the regulation of trunk NCC migration and formation of the DRG by SDF-1-CXCR4 signaling are of potential biomedical importance.