Investigation of asymmetric signaling complexes in axon guidance.

描述(由申请人提供)：生长锥体指导对于建立神经元之间的适当连接至关重要，在这一过程中失败可能会导致精神和神经疾病。几种细胞外引导信号及其受体已被认为与生长锥引导有关。然而，调节对这些线索的反应的细胞内机制还不是很清楚。Rac GTP酶的激活被认为是引导信号转导的关键步骤。然而，我们对RAC激活下游事件的了解是有限的。最近的工作表明，MIG-10/lamelLipodin在引导反应过程中是RAC的效应器。RAC的激活触发了与MIG-10/lamelLipodin的结合以及MIG-10/lamelLipodin的不对称定位，以响应指导提示。这项应用的直接目标是确定MIG-10/lamellipdin信号通路的更多成员。对这些蛋白质的鉴定将为更大的研究应用提供初步数据，该应用将寻求确定信号复合体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提示的定向反应。 与公共健康相关：编码RAC信号通路组成部分的基因突变可能会导致人类智力低下。此外，RAC失活与阻止神经元再生的抑制性信号通路有关。因此，了解RAC和MIG-10/lamellipdin如何控制轴突生长和指导将有助于治疗智力低下和神经损伤。

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.