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。它们为生长锥的导航提供方向信息，并通过特定的受体和信号传导途径吸引或排斥轴突。非典型PKC （aPKC）是神经上皮细胞顶基（a -b）极性信号的关键组成部分，介导Wnt吸引和中线交叉后脊髓联合轴突的前向转向，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）信号组分也需要相互连接轴突的A-P引导。更新提案将研究这两种上皮极性信号通路是否参与介导A-P轴突引导中的Wnt信号，如果是，这两种通路如何整合。生长锥引导的细胞机制，特别是膜运输及其与微管动力学的关系，目前尚未得到充分研究。本提案将解决膜运输和微管动力学在生长锥引导中的作用。此外,

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.