Characterizing Wnt Signaling pathways in Axon Guidance

描述(由申请人提供)：WNT家族蛋白在神经系统连接过程中的轴突路径和目标选择中发挥重要作用。它们为导航生长锥体提供方向信息，并通过特定的受体和信号途径发出信号来吸引或排斥轴突。非典型PKC(APKC)是神经上皮细胞顶基(A-B)极性信号的重要组成部分，它介导了脊髓连合轴突在中线交叉后的Wnt吸引和前向翻转，是轴突引导研究的模型系统。初步结果表明，核心Wnt/平面细胞极性(Wnt/PCP)信号成分也是连合轴突A-P引导所必需的。更新建议将调查这两条上皮极性信号通路是否参与了A-P轴突引导中的Wnt信号传导，如果是，这两条通路是如何整合的。生长锥引导的细胞机制，特别是膜转运及其与微管动力学的关系，目前还没有得到充分的研究。这项建议将解决膜运输和微管动力学在生长锥体引导中的作用。此外, Wnt信号在大脑连接和功能回路形成中的作用仍然知之甚少。 这项提议将使用脑干单胺能轴突作为研究WNTS如何 组织不同的大脑回路来控制行为。目的1：Wnt信号和A-P轴突引导中PCP和aPKC/A-B极性信号成分的特征。目的2：PCP和PKCz/A-B极性信号通路在生长锥引导中的细胞机制。目的3：Wnt信号在大脑回路连接中的作用。WNTs是一个蛋白质大家族(19个成员)，有三类不同的受体，Frizzleds(10个成员)，Ryk和ROR2，都在神经系统中广泛表达。WNT导航系统可能在布线中发挥重要作用。WNT引导系统在成人脊髓损伤后重新诱导，并调节成人皮质脊髓束轴突的再生。建议数 研究将加深对中枢神经系统轴突分子和细胞机制的理解 发育中的连接以及提供创伤后神经系统再生的工具 中枢神经系统的损伤和变性。 公共卫生相关性：WNT引导系统在中枢神经系统连接中发挥重要作用，在成人脊髓损伤后重新诱导，并调节成人皮质脊髓束轴突的再生。这些研究将加深对中枢神经系统轴突在发育过程中分子和细胞机制的理解，并为中枢神经系统损伤和变性后的神经系统再生提供工具。

DESCRIPTION (provided by applicant): Wnt family proteins play important roles in axon pathfinding and target selection during the wiring of the nervous system. They provide directional information for the navigating growth cones and either attract or repel axons by signaling through specific receptors and signaling ways. Atypical PKC (aPKC), a key component of apical-basal (A-B) polarity signaling in neural epithelial cells, mediates Wnt attraction and anterior-directed turning of spinal cord commissural axons after midline crossing, a model system for axon guidance studies. Preliminary results showed that core Wnt/planar-cellpolarity (Wnt/PCP) signaling components are also required for A-P guidance of commissural axons. The renewal proposal will investigate whether the two epithelial polarity-signaling pathways are involved in mediating Wnt signaling in A-P axon guidance and, if so, how the two pathways are integrated. The cellular mechanisms of growth cone guidance, particularly membrane trafficking and its relationship with microtubule dynamics, are currently understudied. This proposal will tackle the role of membrane trafficking and microtubule dynamics in growth cone guidance. In addition, the role of Wnt signaling in brain wiring and formation of functional circuits are still poorly known. This proposal will use the brainstem monoaminergic axons as an inroad to study how Wnts organize distinct brain circuits to control behavior. Aim 1: Characterization of PCP and aPKC/A-B polarity signaling components in Wnt signaling and A-P axon guidance. Aim 2: Cellular mechanisms of PCP and PKCz/A-B polarity signaling pathways in growth cone guidance. Aim 3: Role of Wnt signaling in brain circuit wiring. Wnts are large family of proteins (19 members) with three diverse classes of receptors, the Frizzleds (10 members), Ryk and ROR2, all widely expressed in the nervous system. The Wnt guidance system likely plays major roles in wiring. The Wnt guidance system is re-induced after injury in adult spinal cord and regulates adult corticospinal tract axon regeneration. The proposed studies will enhance the understanding of the molecular and cellular mechanisms of CNS axon wiring in development as well as provide tools for nervous system regeneration following traumatic injury and degeneration of the CNS. PUBLIC HEALTH RELEVANCE: The Wnt guidance system plays important roles in central nervous system wiring and is re-induced after injury in adult spinal cord and regulates adult corticospinal tract axon regeneration. The proposed studies will enhance the understanding of the molecular and cellular mechanisms of CNS axon wiring in development as well as provide tools for nervous system regeneration following traumatic injury and degeneration of the CNS.