Investigation of asymmetric signaling complexes in axon guidance.

描述（由申请人提供）：生长锥引导对于建立神经元之间的适当连接至关重要，该过程中的失败可能导致精神病和神经疾病。 几种细胞外的指导线索和它们的受体已经被牵连在生长锥的指导。 然而，介导对这些线索的反应的细胞内机制还没有很好地理解。 Rac GT3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，在指导反应期间，β-10/片状脂质蛋白作为Rac的效应物。 Rac的激活触发结合到β-10/片状脂质蛋白和β-10/片状脂质蛋白的不对称定位，以响应于引导信号。 本申请的直接目标是鉴定β-10/片状脂质蛋白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，该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方向性反应。 公共卫生相关性：编码Rac信号通路组分的基因突变可导致人类智力迟钝。 此外，Rac失活已涉及阻止神经元再生的抑制性信号传导途径。 因此，了解Rac和β-10/lamellipodin如何控制轴突生长和指导，将有助于治疗精神发育迟滞和神经损伤。

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.