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

基本信息

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
项目类别：
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

项目摘要

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.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以出现在其他 CRISP 条目中列出的机构是。对于中心来说，它不一定是研究者的机构。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 发出的信号在躯干神经嵴细胞向背根神经节 (DRG) 迁移中的作用。以下假设：[1] 趋化因子引导受体 CXCR4 在以不同的时空模式迁移到 DRG 的过程中在神经嵴细胞中表达，而其激活配体 SDF-1 则沿着神经嵴迁移途径；[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向发育中的 DRG 的迁移改变；[3] CXCR4 趋化因子受体及其激活配体 SDF 的表达； -1，受 TGF¿超家族成员 BMP4 和 TGF¿ 1，分别；[4] SDF-1/CXCR4 信号传导的下游效应控制胚胎发生期间神经嵴细胞向 DRG 的迁移，由磷脂酰肌醇 3 磷酸化信号转导途径介导。神经嵴是一个祖细胞群，有助于形成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 通过其特定受体 CXCR4 发出信号，是许多干细胞和祖细胞群从各自出现部位迁移到分化为复杂组织和器官的区域所必需的。整个 CXCR4 的删除。或 SDF-1 基因导致小鼠在妊娠 18.5 天左右因小脑、心脏和造血缺陷而导致围产期死亡。该研究计划的总体目标是确定。胚胎发生过程中躯干神经嵴细胞迁移至 DRG 是否需要趋化因子 SDF-1，以及 SDF-1 对其特定受体 CXCR4 信号传导的破坏是否会导致神经嵴迁移改变和/或 DRG 形成异常该研究计划还将研究 TGF 对 SDF-1 和 CXCR4 表达的调节。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，胚胎中的BMP 1和BMP4。是在胚胎发育中发挥重要作用的两个因素，并在培养的多种成体细胞类型中调节 SDF-1 和 CXCR4 的表达。最后，该研究计划将研究 SDF-1/CXCR4 信号传导在胚胎神经过程中是否具有下游影响。嵴细胞向 DRG 的迁移是由磷脂酰肌醇 3 磷酸化信号转导途径介导的。 SDF-1 - CXCR4 趋化因子信号轴功能性失活后，小鼠和斑马鱼的周围神经系统发育异常，表明 CXCR4/SDF-1 在胚胎发生过程中躯干神经嵴细胞迁移至形成的 DRG 中发挥作用。鉴于在瓦登堡-先天性巨结肠症和先天性巨结肠症等疾病中异常 DRG 和感觉神经元发育造成的有害生理缺陷，目前几乎没有可用的机制信息。 WHIM，通过 SDF-1-CXCR4 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。