REGULATION OF NEURAL CREST CELL MIGRATION BY SDF1-CXCR4 SIGNALING

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们计划研究趋化因子基质细胞衍生因子-1（SDF-1）通过其特异性受体CXCR 4在躯干神经嵴细胞向背根神经节（DRG）迁移中的信号传导作用。本研究将探讨以下假设：[1]趋化因子导向受体CXCR 4在神经嵴细胞向DRG迁移的过程中以不同的时空模式表达，而其活化配体SDF-1则沿着神经嵴迁移的途径表达;[2]胚胎发生过程中SDF-1/CXCR信号传导功能的丧失导致神经嵴细胞迁移到发育中的DRG的改变;[3] CXCR 4趋化因子受体及其活化配体SDF-1的表达分别由TGF <$超家族成员BMP 4和TGF <$1调节; [4] SDF-1/CXCR 4信号传导的下游效应在胚胎发生期间控制神经嵴细胞向DRG的迁移，由磷脂酰肌醇-3磷酸化信号传导途径介导。 神经嵴是一个祖细胞群，有助于多种细胞和组织类型，包括DRG和感觉神经系统。趋化因子SDF-1通过其特异性受体CXCR 4的信号传导是许多干细胞和祖细胞群体从其各自的出现部位迁移到它们将分化成复杂组织和器官的区域所必需的。在小鼠中，由于小脑、心脏和造血缺陷，整个CXCR 4或SDF-1基因的缺失导致大约妊娠第18.5天的围产期死亡。这项研究计划的全球目标是确定趋化因子SDF-1是否是胚胎发生过程中躯干神经嵴细胞迁移到DRG所必需的，以及SDF-1对其特异性受体CXCR 4的信号传导的破坏是否会导致神经嵴迁移和/或DRG的异常形成。该研究计划还将研究在神经嵴细胞从神经管背侧迁移和神经嵴细胞迁移到背根神经节期间，TGF？1和BMP 4对胚胎中SDF-1和CXCR 4表达的调节。BMP和TGF？是在胚胎发育中起重要作用的两个因子，并且调节培养中多种成体细胞类型中SDF-1和CXCR 4的表达。最后，研究计划将调查SDF-1/CXCR 4信号在胚胎神经嵴细胞迁移到DRG的下游效应是否由磷脂酰肌醇-3磷酸化信号转导通路介导。 在SDF-1 -CXCR 4趋化因子信号传导轴功能失活后，小鼠和斑马鱼外周神经系统发育异常，提示CXCR 4/SDF-1在胚胎发生期间在躯干神经嵴细胞迁移至形成DRG中的作用。 然而，目前几乎没有任何机械信息。鉴于在诸如Waardenburg-Hirschsprung病和WHIM的病症中由异常DRG和感觉神经元发育引起的有害生理缺陷，通过SDF-1-CXCR 4信号传导调节躯干NCC迁移和DRG形成的研究具有潜在的生物医学重要性。

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.