Regulation of Neuronal Lamination and Dendritogenesis by Reelin-Dab1 Signaling

描述（由申请人提供）：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精细化的理解存在重大差距。Reelin-Dab 1通路是神经元分层和树突发生所必需的。对Reelin神经元反应的新见解将扩大我们对脑分层和树突扩张的细胞控制的理解。我们的初步研究结果表明，Stk 25是这一途径的修饰剂，定位于高尔基体，与LKB 1- STRAD细胞极性途径相互作用，并调节神经元极化。Stk 25过表达导致多个轴突形成，这被Reelin信号转导抑制，并且还抑制了新鉴定的对Reelin的反应：高尔基体向树突的部署。这些新发现表明Reelin-Dab 1信号和Stk 25在调节神经元极化和高尔基体部署中的竞争作用。 基于此，我们假设Reelin-Dab 1，Stk 25和LKB 1-STRAD信号之间的竞争指导神经元分层和树突状细胞生成，部分通过调节高尔基体部署。这一假设将通过追求以下具体目标来解决：1。确定LKB 1-STRAD-STK 25信号传导是否拮抗Reelin-Dab 1信号传导，以指导发育过程中的脑分层、树突发生和高尔基体部署。2.确定大脑分层和神经元极化的效应器是否调节高尔基体的部署。 通过操纵野生型和dab 1缺陷脑中的Stk 25和LKB 1-STRAD表达，将确定这些基因如何指导神经元分层和/或树突发生。将研究已知的Reelin-Dab 1和Stk 25信号传导效应子在高尔基体部署中的作用，以揭示这种活性的分子控制，这将为解决其在神经元发育中的作用提供重要信息。拟议的研究将提供深入了解如何由细胞外信号调节的两个竞争途径指导体内脑分层和树突状细胞生成。此外，它将提供新的线索，分子控制树突状高尔基体部署。

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.