Role of Endothelins in SCG axon guidance

内皮素在 SCG 轴突引导中的作用

• 批准号: 7940854
• 负责人: Takako Makita
• 金额: $ 24.82万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7940854
• 关键词: Address; Alleles; Arteries; Axon; Blood Vessels; Carotid Arteries; Cell Lineage; Cells; Cervical; Coculture Techniques; Cues; Defect; Development; Embryo; Endothelin; Endothelin Receptor; Exhibits; External carotid artery structure; Future; Genetic; Goals; In Vitro; Internal carotid artery structure; Lead; Ligands; Mesoderm Cell; Modeling; Molecular; Mutant Strains Mice; Nerve; Nervous system structure; Neurobiology; Neurologic; Neurons; Organ; Organ Transplantation; Phase; Phenotype; Process; Production; Publishing; Receptor Gene; Role; Route; Signal Transduction; Smooth Muscle; Structure of superior cervical ganglion; Testing; Tissues; Uncertainty; Vascular Smooth Muscle; axon guidance; base; endothelin-converting enzyme; in vitro Assay; mutant; prevent; receptor; receptor function; research study; retinal rods

A key process In deyelopnnental neurobiology is theimanner by which axons projecting from newly born neurons cHoose paths to reach and Innen/atedistarit target organs. In general, this process Is thought to involve cues that direct axonal outgrowth along specific routes. Hoyvever, only a limited number of guidance cues are known, far less than sufficient to explain the complexity of nnamnriial|an nervous system. This proposal addresses the role of endothelin signaling as a ciritical mechanism that controls the projection of sympathetic axons from the superior cervical gariglia (SGG), New observations described in detail in this proposal lead to a model in which vascular smooth muiscle-derived endothelihs provide guidance cues for sympathetic axons from the SCG to take a specific ^ascular trajectory, along the external Carotid artery. A subset of SCG neurons express the type A endothelin receptor (ETA), and the normal function of this receptor is essential for SCG axons to choose between distinct trajectories and to ultimately innervate their appropriate target tissues. In this application, I propose experiments to address and extend a model in which endothelin signaling, emanating from smooth muscle ofthe external carotid arteries, is a required guidance cuefdrSCG axons. Specific Aim1: To define the genetic requirements for endothelin signaling coitiRonents in SeG axon guidance. This aim addresses the niechanisrn Of endothelin ligand production by smoothmuscle specifically of the external carotid arteries. Specific Aim 2: To define the tissue-specific functions of endothelin signaling components in SGG axon guidance. This aim address the extent to which ETA is intrinsically required by SGG neurons to respond endothelins in order to project along the external carotid arteries. Specific Aim3: To define the molecular basis of defective SCG outgrowth in H0xa3 mutant mice. In this aim, I will evaluate how expression of endothelin signaling; components iis perturbed in Hoxa3 mutant mice, which have a comparable SCG outgrowth deficiency as seen in ETA-deficient embryos

发育神经生物学中的一个关键过程是新生神经元投射的轴突选择到达目标器官的路径的方式。一般来说，这个过程被认为涉及引导轴突沿着特定路线生长的线索。然而，目前已知的引导线索数量有限，远远不足以解释神经系统的复杂性。 该提案阐述了内皮素信号传导作为控制交感神经轴突从上颈加里格利亚（SGG）投射的关键机制的作用，该提案中详细描述的新观察结果产生了一个模型，其中血管平滑肌衍生的内皮细胞提供指导提示来自 SCG 的交感神经轴突沿着颈外动脉采取特定的血管轨迹。 SCG 神经元的一部分表达 A 型内皮素受体 (ETA)，该受体的正常功能对于 SCG 轴突在不同的轨迹之间进行选择并最终支配其适当的靶组织至关重要。 在此应用中，我提出实验来解决和扩展一个模型，其中源自颈外动脉平滑肌的内皮素信号传导是 fdrSCG 轴突所需的引导信号。 具体目标 1：确定 SeG 轴突中内皮素信号传导协同体的遗传要求 指导。这一目标解决了平滑肌（特别是颈外动脉）产生内皮素配体的机制。 具体目标 2：定义 SGG 轴突引导中内皮素信号传导成分的组织特异性功能。这一目标解决了 SGG 神经元响应内皮素以沿着颈外动脉投射所需的 ETA 程度。 具体目标 3：确定 H0xa3 突变小鼠 SCG 生长缺陷的分子基础。为此，我将评估内皮素信号传导的表达方式； Hoxa3 突变小鼠中的 i 成分受到干扰，这些小鼠具有与 ETA 缺陷胚胎中类似的 SCG 生长缺陷