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布线过程中的轴突寻路和靶标选择中发挥重要作用。它们为生长锥导航提供方向信息，并通过特定的受体和信号传导途径发出信号，吸引或排斥轴突。非典型蛋白激酶C（aPKC）是神经上皮细胞顶-基底（A-B）极性信号的关键成分，介导Wnt吸引和脊髓连合轴突穿越中线后的前向转向，是轴突导向研究的模型系统。初步结果表明，核心Wnt/平面细胞极性（Wnt/PCP）信号组件也需要连合轴突的A-P指导。更新建议将调查是否两个上皮极性信号通路参与介导Wnt信号在A-P轴突的指导，如果是这样，这两个途径是如何整合。细胞机制的生长锥的指导，特别是膜运输及其与微管动力学的关系，目前正在研究。这项提议将解决膜运输和微管动力学在生长锥指导中的作用。此外，本发明还提供了一种方法， Wnt信号在脑布线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Wnt如何作用的切入点。 组织不同的大脑回路来控制行为。目的1：研究PCP和aPKC/A-B极性信号成分在Wnt信号和A-P轴突导向中的作用。目的2：PCP和PKCz/A-B极性信号通路在生长锥导向中的细胞机制。目的3：Wnt信号在脑回路布线中的作用。Wnt是一个蛋白质大家族（19个成员），具有三种不同类型的受体，Frizzleds（10个成员），Ryk和ROR 2，都广泛表达于神经系统中。Wnt制导系统可能在布线中起主要作用。Wnt引导系统在成年脊髓损伤后被重新诱导并调节成年皮质脊髓束轴突再生。拟议 这些研究将加深对中枢神经系统轴突的分子和细胞机制的理解， 以及为创伤后神经系统再生提供工具 中枢神经系统的损伤和退化。 公共卫生相关性：Wnt引导系统在中枢神经系统的布线中起重要作用，在成年脊髓损伤后被重新诱导，并调节成年皮质脊髓束轴突再生。拟议的研究将提高CNS轴突布线在发展中的分子和细胞机制的理解，以及提供工具的创伤性损伤和CNS变性后的神经系统再生。

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.