Characterizing Wnt signaling pathways in axon guidance

描述（由申请人提供）：神经系统由大量神经元组成，这些神经元精确地连接成一个复杂的网络，为所有行为提供解剖学基础。神经回路的异常发育可能导致各种神经和精神障碍。长期目标是了解功能性神经系统布线过程中轴突引导的分子和细胞机制。这项研究的发现也将为成年中枢神经系统损伤后的轴突再生研究提供线索。轴突沿着中枢神经系统的前后轴（大脑和脊髓之间的连接）沿着布线的机制一直是一个长期的谜。Wnt-卷曲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蛋白的反应性的生长锥信号传导机制是未知的。目前已知三种途径介导Wnt作用：经典β-连环蛋白途径、平面细胞极性（PCP）途径和Ca++/PKC途径。这项资助计划使用连合轴突作为模型系统来测试PCP通路（Aim 1），PKC通路（Aim 2）和经典通路以及潜在的新通路（Aim 3）在轴突指导中的作用。这项资助还将探索一种以上的途径可能参与指导事件的不同方面的可能性，推进对轴突指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布线提供了更多的机会。拟议的研究将为未来关于感觉通路如何被引导向前投射（从脊髓到大脑）和运动通路如何向后投射（从大脑到脊髓）的机制的研究提供基础，并且还可以解决Wnt梯度在中枢神经系统中图案化神经元网络中的生物学作用。

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.