REGULATION OF NEURAL CREST CELL MIGRATION BY SDF1-CXCR4 SIGNALING

SDF1-CXCR4 信号传导对神经嵴细胞迁移的调节

• 批准号: 7959957
• 负责人: Ratnam Sathiagana Seelan
• 金额: $ 27.8万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959957
• 关键词: Adult; Afferent Neurons; BMP4; CXCR4 Receptors; CXCR4 gene; Cardiac; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; Defect; Development; Dorsal; Embryo; Embryonic Development; Emigrations; Funding; Genes; Grant; Hematopoietic; Histocompatibility Testing; Immigration; Institution; Investigation; Ligands; Mediating; Molecular; Mus; Nervous system structure; Neural Crest; Neural Crest Cell; Neural tube; Organ; Pathway interactions; Pattern; Perinatal; Peripheral Nervous System; Phosphorylation; Physiological; Play; Population; Regulation; Research; Research Personnel; Resources; Role; Sensory; Signal Transduction; Signal Transduction Pathway; Site; Source; Spinal Ganglia; Stem cells; Stromal Cell-Derived Factor 1; Time; Tissues; United States National Institutes of Health; Waardenburg-Hirschsprung disease; Zebrafish; cell motility; cell type; chemokine; chemokine receptor; loss of function; member; migration; neuron development; programs

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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 我们计划通过其特异性受体CXCR4在质基质细胞衍生的因子1（SDF-1）中研究信号传导在树干神经元细胞向背根神经节（DRG）迁移中的特定受体CXCR4的作用。该研究将研究以下假设：[1]趋化因子引导受体CXCR4在迁移到DRG中以不同的时空模式在神经元细胞中表达，而其激活的配体SDF-1，沿着神经元crest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元细胞细胞迁移到发育中的DRG中； [3] CXCR4趋化因子受体及其激活配体SDF-1的表达分别受TGF¿超家族成员bmp4和tgf¿1的调节。 [4] SDF-1/CXCR4信号传导的下游效应，该信号在胚胎发生过程中控制神经rest细胞向DRG的迁移，是由磷脂酰肌醇-3磷酸化信号转导途径介导的。 神经rest是一种祖细胞群，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通过其特定接收器的信号传导，CXCR4是许多干细胞和祖细胞群体从各自的出现部位迁移到将它们区分为复杂组织和器官的区域所必需的。在大约妊娠第18.5天，由于小脑，心脏和造血缺陷，在大约妊娠第18.5天，整个CXCR4或SDF-1基因的删除会导致围产期致死性。该研究计划的全球目的是确定趋化因子SDF-1在胚胎发生过程中是否需要将树干神经元细胞迁移到DRG，以及SDF-1信号传导对其特定受体CXCR4的破坏是否会导致神经元的迁移和/或DRG的异常形成改变。该研究计划还将在神经管的背面神经元细胞迁移期间，在胚胎中通过TGF¿1和BMP4调节胚胎中的SDF-1和CXCR4表达，并调节神经管和神经元细胞迁移到背部根神经的背面。 BMP和TGF¿是两个因素在胚胎发育中起重要作用，并在各种成人细胞类型的培养中调节SDF-1和CXCR4表达。最后，研究计划将研究胚胎中性rest细胞迁移到DRG期间SDF-1/CXCR4信号传导的下游效应是否是由磷脂酰肌醇-3磷酸化信号转导途径介导的。 SDF-1-CXCR4趋化因子信号轴功能失活后，小鼠和斑马鱼的外周神经系统的异常发育表明CXCR4/SDF-1在胚胎发生过程中CXCR4/SDF-1在躯干神经元细胞向形成DRG的躯干神经元细胞迁移中的作用。但是，目前几乎没有机械信息。鉴于Waardenburg-Hirschsprung疾病等条件异常的DRG和感觉神经元发育引起的微妙的身体缺陷，以及对SDF-1-CXCR4信号的TRUNK NCC迁移和DRG形成的调节的研究具有潜在的生物医学重要性。