Regulation of Neuronal Lamination and Dendritogenesis by Reelin-Dab1 Signaling

描述(由申请人提供)：在我们对调节神经元定位的分子和细胞控制以及随后建立神经回路的神经突起的详细描述方面存在着显著的差距。Reelin-Dab1通路是神经元分层和树突形成所必需的。对神经元对Reelin的反应的新见解将扩大我们对大脑分层和树突扩张的细胞控制的理解。我们的初步发现表明，STK25是该通路的修饰者，定位于高尔基体，与LKB1-STRAD细胞极性通路相互作用，并调节神经元极化。STK25的过表达导致多个轴突的形成，这被Reelin信号抑制，也抑制了新发现的对Reelin的反应：高尔基体部署到树突。这些新的发现表明，Reelin-Dab1信号和STK25在调节神经元极化和高尔基体部署中具有竞争性作用。在此基础上，我们假设Reelin-Dab1、STK25和LKB1-Strad信号之间的竞争部分通过调节高尔基体的部署来指导神经元的分层和树突的发生。这一假说将通过追求以下具体目标来解决：1.确定LKB1-Strad-STK25信号是否拮抗Reelin-Dab1信号，以指导发育过程中的大脑分层、树突发生和高尔基体部署。2.确定脑板层和神经元极化效应因子是否调节高尔基体的分布。通过操纵STK25和LKB1-Strad在野生型和dab1缺陷脑中的表达，将确定这些基因如何指导神经元分层和/或树突形成。已知的Reelin-Dab1和STK25信号效应器将被研究在高尔基体部署中的作用，以揭示这一活动的分子控制，这将为解决其在神经元发育中的作用提供必要的信息。这项拟议的研究将深入了解细胞外信号调控的两条相互竞争的通路如何在体内指导大脑分层和树突形成。此外，它还将为树突状高尔基体部署的分子调控提供新的线索。

DESCRIPTION (provided by applicant): Significant gaps exist in our understanding of the molecular and cellular controls that regulate neuronal positioning and the subsequent neurite elaborations that establish neural circuits. The Reelin-Dab1 pathway is required for neuronal lamination and dendritogenesis. New insights into the neuronal response to Reelin will expand our understanding of the cellular control of brain lamination and dendrite expansion. Our preliminary findings show that Stk25 is a modifier of this pathway that localizes to the Golgi, interacts with the LKB1- STRAD cell polarity pathway, and regulates neuronal polarization. Stk25 overexpression causes multiple axon formation, which is suppressed by Reelin signaling, and also suppresses a newly identified response to Reelin: the deployment of the Golgi into dendrites. These new findings suggest competitive roles for Reelin-Dab1 signaling and Stk25 in the regulation of neuronal polarization and Golgi deployment. Based on this, we hypothesize that competition among Reelin-Dab1, Stk25 and LKB1-STRAD signaling instructs neuronal lamination and dendritogenesis, in part by regulating Golgi deployment. This hypothesis will be addressed by pursuing the following specific aims: 1. Determine if LKB1-STRAD-STK25 signaling antagonizes Reelin-Dab1 signaling to instruct brain lamination, dendritogenesis, and Golgi deployment during development. 2. Determine if effectors of brain lamination and neuronal polarization regulate Golgi deployment. By manipulating Stk25 and LKB1-STRAD expression in wild-type and dab1-deficient brains, it will be determined how these genes instruct neuronal lamination and/or dendritogenesis. Known effectors of Reelin-Dab1 and Stk25 signaling will be investigated for roles in Golgi deployment to uncover the molecular control of this activity, which will provide essential information towards resolving its role in neuronal development. The proposed research will offer insight into how two competing pathways regulated by extracellular signals instruct brain lamination and dendritogenesis in vivo. In addition, it will provide novel clues about the molecular control of dendritic Golgi deployment.