REGULATION OF NEURAL CREST CELL MIGRATION BY SDF1-CXCR4 SIGNALING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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CXCR4在主干神经脊细胞向背根神经节(DRG)迁移中的信号作用。本研究将探讨以下假设：(1)趋化因子导向受体CXCR4在迁移到背根节的过程中以不同的时空模式在神经脊细胞中表达，而其激活配体SDF-1则沿着神经脊迁移的途径表达；(2)胚胎发育过程中SDF-1/CXCR信号的功能丧失导致神经脊细胞向发育中的背根节迁移；(3)CXCR4趋化因子受体及其激活配体SDF-1的表达分别受转化生长因子超家族成员BMP4和转化生长因子β1的调节；[4]在胚胎发育过程中，SDF-1/CXCR4信号调控神经脊细胞向背根节的迁移，其下游效应是通过磷脂酰肌醇-3磷酸化信号转导途径介导的。 神经脊是一个祖细胞群体，为多种细胞和组织类型做出贡献，包括背根节和感觉神经系统。趋化因子SDF-1通过其特定的受体CXCR4发出信号，是许多干细胞和祖细胞群体从各自的出现部位迁移到它们将分化为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CXCR4或SDF-1基因的缺失会导致大约18.5天的围产儿死亡。本研究的总体目标是确定在胚胎发育过程中，是否需要趋化因子SDF-1将主干神经脊细胞迁移到背根节，以及SDF-1信号与其特定受体CXCR4的干扰是否会导致神经脊迁移改变和/或DRG的异常形成。该研究计划还将研究转化生长因子1和骨形成蛋白4对胚胎中SDF-1和CXCR4表达的调节，即神经脊细胞从神经管的背侧向背根神经节迁移的过程。骨形态发生蛋白和转化生长因子β是在胚胎发育中起重要作用的两个因子，它们在培养的各种成体细胞中调节SDF-1和CXCR4的表达。最后，该研究计划将研究SDF-1/CXCR4信号在胚胎神经脊细胞向DRG迁移过程中的下游作用是否由磷脂酰肌醇-3磷酸化信号转导途径介导。 在小鼠和斑马鱼中，由于SDF-1-CXCR4趋化因子信号轴的功能失活，导致了周围神经系统的异常发育，这表明CXCR4/SDF-1在胚胎发育期间躯干神经脊细胞迁移到形成DRG的过程中发挥了作用。然而，目前几乎没有机械性的信息。鉴于在Waardenburg-Hirschsprung病和WHIM等疾病中，DRG异常和感觉神经元发育所造成的有害生理缺陷，研究SDF-1-CXCR4信号对躯干NCC迁移和DRG形成的调控具有潜在的生物医学意义。

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.