Role of Endothelins in SCG axon guidance

发育神经生物学中的一个关键过程是从新生神经元伸出的轴突选择路径到达并进入靶器官的方式。一般来说，这一过程被认为涉及到引导轴突沿沿着特定路线生长的线索。然而，只有有限数量的指导线索是已知的，远远不足以解释nnamnrial的复杂性|神经系统 该提议解决了内皮素信号传导作为控制交感神经轴突从上级颈动脉（SGG）投射的关键机制的作用。在该提议中详细描述的新观察导致了一个模型，其中血管平滑肌衍生的内皮为来自SCG的交感神经轴突提供引导线索，以沿着颈外动脉沿着采取特定的血管轨迹。SCG神经元的一个子集表达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，我提出实验来解决和扩展一个模型，其中内皮素信号，从颈外动脉平滑肌发出，是一个必要的指导线索drSCG轴突。 具体目的1：明确SeG轴突中内皮素信号通路的遗传要求 指导本研究的目的是探讨颈外动脉平滑肌产生内皮素配体的机制。 具体目标2：确定内皮素信号传导组分在SGG轴突引导中的组织特异性功能。该目的解决了SGG神经元响应内皮素以沿颈外动脉沿着投射的内在需要ETA的程度。 具体目标3：确定H 0xa 3突变小鼠中SCG生长缺陷的分子基础。在这个目标中，我将评估内皮素信号传导的表达; Hoxa 3突变小鼠中的组分i是如何被扰乱的，这些小鼠具有与ETA缺陷胚胎中所见的相当的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