Characterizing Wnt signaling pathways in axon guidance

描述(申请人提供)：神经系统由大量神经元组成，精确地连接成一个复杂的网络，为所有行为的解剖学基础服务。神经回路的异常发育可能导致各种神经和精神障碍。长期目标是了解在功能神经系统连接过程中轴突引导的分子和细胞机制。这项拟议研究的发现还将为成人中枢神经系统损伤后轴突再生的研究提供线索。轴突沿着中枢神经系统(大脑和脊髓之间的连接)的前后轴连接的机制一直是一个谜。WNT-Frizzleed信号最近被证明是脊髓连合轴突的A-P引导所必需的。然而，介导对Wnt蛋白应答的生长锥信号机制尚不清楚。目前已知有三条途径介导Wnt的作用：典型的β-连环蛋白途径、平面细胞极性(PCP)途径和Ca++/PKC途径。这项资助建议以连合轴突为模型系统，测试PCP通路(Aim1)、PKC通路(Aim2)以及规范通路和潜在的新通路(Aim3)在轴突引导中的作用。这项资助还将探索不止一条途径可能涉及引导事件的不同方面，促进对轴突引导的细胞机制的理解。Wnt蛋白可以作为轴突引导线索的发现为理解大脑连接提供了更多的机会。这些研究将为进一步研究感觉通路如何被引导向前方(从脊髓到脑)投射以及运动通路如何被引导向后方(从大脑到脊髓)投射的机制提供基础，并可能解决Wnt梯度在中枢神经系统神经元网络图案化中的生物学作用。

DESCRIPTION (provided by applicant): The nervous system is composed of an enormous number of neurons, precisely connected into an intricate network, subserving the anatomical basis for all behaviors. Abnormal development of neural circuitry may cause various neurological and mental disorders. The long-term objective is to understand the molecular and cellular mechanisms of axon guidance during the wiring of the functional nervous system. The discovery of the proposed research will also provide clues for axonal regeneration studies following injury in the adult central nervous system. The mechanisms of axon wiring along the anterior-posterior axis of the central nervous system (the connections between the brain and the spinal cord) have remained a long-standing mystery. Wnt-Frizzled signaling was recently shown required for the A-P guidance of spinal cord commissural axons. However, the growth cone signaling mechanisms that mediate responsiveness to Wnt proteins are unknown. Three pathways are currently known to mediate Wnt actions: the canonical beta-catenin pathway, the planar cell polarity (PCP) pathway and the Ca++/PKC pathway. This grant proposes to test the role of the PCP pathway (Aim1), the PKC pathway (Aim2) and the canonical pathway and potentially novel pathways (Aim3) in axon guidance using commissural axons as a model system. This grant will also explore the possibility that more than one pathway might be involved in different aspects of guidance events, advancing the understanding cellular mechanisms of axon guidance. The finding that Wnt proteins can act as axon guidance cues provides more opportunity for understanding brain wiring. The proposed studies will provide foundation for future studies on the mechanisms how sensory pathways are guided to project anteriorly (from the spinal cord to the brain) and motor pathways to project posteriorly (from the brain to the spinal cord) and may also address the biological role of Wnt gradients in patterning neuronal networks in the central nervous system.