Role of endothelins in SCG axon guidance

描述（由申请人提供）： 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到达和支配靶器官的路径的方式。该提议提出内皮素信号传导作为控制交感神经轴突从上级颈神经节（SCG）投射的关键机制的作用。在这个提议中描述的新的观察导致一个模型，其中血管平滑肌衍生的内皮素提供引导线索，从SCG的交感神经轴突采取特定的血管轨迹，沿着颈外动脉。SCG神经元的子集表达A型内皮素受体（ETA），其对于SCG轴突在不同轨迹之间进行选择并支配其适当的靶组织是必不可少的。在这个应用中，我提出的实验，以解决和扩展的模型中，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SCG轴突。 具体目标1：明确SCG轴突导向中内皮素信号组分的遗传要求。这一目标解决了内皮素配体的生产机制，特别是颈外动脉的平滑肌。 具体目标2：确定内皮素信号传导组分在SCG轴突引导中的组织特异性功能。这个目标解决了在何种程度上ETA是内在需要的SCG神经元响应内皮素，以项目沿着颈外动脉。 具体目标3：确定Hoxa 3突变小鼠中SCG生长缺陷的分子基础。在这一目标中，我将评估如何表达内皮素信号成分的Hoxa 3突变小鼠，这有一个相当的SCG生长缺陷，在ETA缺陷的胚胎中看到的扰动。 公共卫生相关性：本研究探讨了神经-血管一致性的分子基础和发育过程中正确神经回路的建立，这两者都与神经支配的先天性缺陷的治疗以及神经疾病或损伤后神经回路的再生有关。所学到的原则也将适用于器官移植研究，以实现移植器官的切断轴突的神经再支配。

DESCRIPTION (provided by applicant): A key process in developmental neurobiology is the manner by which axons projecting from newly born neurons choose paths to reach and innervate target organs. This proposal addresses the role of endothelin signaling as a critical mechanism that controls the projection of sympathetic axons from the superior cervical ganglia (SCG). New observations described in this proposal lead to a model in which vascular smooth muscle-derived endothelins provide guidance cues for sympathetic axons from the SCG to take a specific vascular trajectory, along the external carotid artery. A subset of SCG neurons express the type A endothelin receptor (ETA), which is essential for SCG axons to choose between distinct trajectories and to 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 of the external carotid arteries, is a required guidance cue for SCG axons. Specific Aim1: To define the genetic requirements for endothelin signaling components in SCG axon guidance. This aim addresses the mechanism of endothelin ligand production by smooth muscle specifically of the external carotid arteries. Specific Aim 2: To define the tissue-specific functions of endothelin signaling components in SCG axon guidance. This aim addresses the extent to which ETA is intrinsically required by SCG 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 Hoxa3 mutant mice. In this aim, I will evaluate how expression of endothelin signaling components is perturbed in Hoxa3 mutant mice, which have a comparable SCG outgrowth deficiency as seen in ETA-deficient embryos. Public health relevance: This research addresses the molecular basis of nerve-blood vessel congruency and the establishment of proper neural circuitry during development, both of which are relevant to the treatment for congenital defects in neural innervations, and for regeneration of neural circuitry following neurological diesease or injury. The principles learned will also apply to organ transplantation studies to achieve reinnervation of amputated axons to transplanted organs.