Role of Endothelins in SCG axon guidance

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和启动靶器官的路径。一般来说，这一过程被认为涉及到引导轴突沿着特定路线生长的线索。Hoyvever，只有有限数量的指导线索是已知的，远远不足以解释命名|一个神经系统的复杂性。 本研究探讨了内皮素信号作为控制颈上神经节(SGG)交感轴突投射的关键机制的作用。本研究中详细描述的新观察结果导致了一个模型，在该模型中，血管平滑的多节样来源的内皮细胞为来自SCG的交感轴突沿着颈外动脉沿特定的血管轨迹提供指导线索。部分SCG神经元表达A型内皮素受体(ETA)，这种受体的正常功能对于SCG轴突在不同的运动轨迹之间进行选择并最终支配其适当的靶组织是必不可少的。 在这个应用中，我提出了一个实验来解决和扩展一个模型，在这个模型中，从颈外动脉的平滑肌肉发出的内皮素信号是SCG轴突所必需的指导。 特异性目的1：确定节段性轴突内皮素信号转导基因的遗传要求 指导。本研究的目的是探讨通过颈外动脉的平滑肌肉产生内皮素配体的机制。 具体目的2：明确SGG轴突引导中内皮素信号成分的组织特异性功能。这个目的是为了解决SGG神经元内在地需要ETA来响应内皮素以便沿着颈外动脉投射的程度。 目的：明确H0xa3突变小鼠SCG突起缺陷的分子基础。在这个目标中，我将评估在hoxa3突变小鼠中，内皮素信号转导组分i的表达是如何受到干扰的，这些突变小鼠与eta基因缺陷的胚胎有类似的scg生长缺陷。

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