Investigation of asymmetric signaling complexes in axon guidance.

描述（由申请人提供）：生长锥引导对于神经元之间建立适当的连接至关重要，这一过程的失败可能导致精神和神经系统疾病。几种细胞外引导线索及其受体与生长锥引导有关。然而，介导对这些线索的反应的细胞内机制尚不清楚。Rac GTPase的激活被认为是引导信号转导的关键步骤。然而，我们对Rac激活下游事件的理解是有限的。最近的研究表明，米格-10/lamellipodin在制导响应过程中是Rac的效应器。Rac的激活触发了与MIG-10/lamellipodin的结合和MIG-10/lamellipodin的不对称定位，以响应引导提示。该应用程序的直接目标是识别米格-10/lamellipodin信号通路的其他成员。这些蛋白质的鉴定将为更大的研究应用提供初步数据，这些研究应用将寻求确定信号复合物的不对称定位是如何建立的，以及这种不对称定位如何导致对指导线索的定向反应。

DESCRIPTION (provided by applicant): Growth cone guidance is critical for the establishment of appropriate connectivity among neurons and failures in this process can result in psychiatric and neurological disease. Several extracellular guidance cues and their receptors have been implicated in growth cone guidance. However, the intracellular mechanisms that mediate the response to these cues are not well understood. Activation of the Rac GTPase is thought to be a key step in the transduction of guidance signals. However, our understanding of the events downstream of Rac activation is limited. Recent work has implicated MIG-10/lamellipodin as an effector for Rac during the guidance response. Activation of Rac triggers binding to MIG-10/lamellipodin and asymmetric localization of MIG-10/lamellipodin in response to a guidance cue. The immediate goal of this application is to identify additional members of the MIG-10/lamellipodin signaling pathway. Identification of these proteins will provide preliminary data for a larger research application that will seek to determine how asymmetric localization of signaling complexes is established and how this asymmetric localization results in directional responses to guidance cues. PUBLIC HEALTH RELEVANCE: Mutations in genes that encode components of the Rac signaling pathway can cause mental retardation in humans. Furthermore, Rac inactivation has been implicated in the inhibitory signaling pathways that prevent neuronal regeneration. Therefore, an understanding of how Rac and MIG-10/lamellipodin function to control axon growth and guidance will be useful in efforts to treat mental retardation and neural injury.