DCC-Mediated Dab1 Phosphorylation Participates in the Multipolar-to-Bipolar Transition of Migrating Neurons
DCC-Mediated Dab1 Phosphorylation Participates in the Multipolar-to-Bipolar Transition of Migrating Neurons
复制标题
DCC 介导的 Dab1 磷酸化参与迁移神经元的多极到双极转变
DOI：
10.1016/j.celrep.2018.03.005
复制
发表时间：
2018
期刊：
影响因子：
8.8
通讯作者：
Zhu Xiao Juan
中科院分区：
文献类型：
--
作者：
Zhang Jian Hua;Zhao Yi Fei;He Xiao Xiao;Zhao Yang;He Zi Xuan;Zhang Lei;Huang Ying;Wang Yu Bing;Hu Ling;Liu Lin;Yu Hua Li;Xu Jia Hui;Lai Ming Ming;Zhao Dong Dong;Cui Lei;Guo Wei Xiang;Xiong Wen Cheng;Ding Yu Qiang;Zhu Xiao Juan
新生的神经元在新皮层发育过程中经历由内而外的迁移到它们的最终目的地。Reelin诱导的Dab 1酪氨酸磷酸化是控制皮层神经元迁移的关键机制。然而，Dab 1的Reelin非依赖性磷酸化的作用仍不清楚。在这里，我们报告，在结直肠癌（DCC）中缺失的Dab 1通过其P3结构域相互作用。Netrin 1是一种DCC配体，诱导Dab 1在Y220和Y232处磷酸化。有趣的是，敲低DCC或截断其P3结构域显着延迟神经元迁移和损害迁移神经元的多极到双极的转变。值得注意的是，迁移延迟和形态转变缺陷是由磷酸模拟Dab 1或组成型活性形式的Fyn原癌基因（Fyn），Src家族酪氨酸激酶的成员，有效地诱导Dab 1磷酸化的表达拯救。总的来说，这些发现说明了一个DCC-Dab 1的相互作用，确保适当的神经元迁移过程中新皮层的发展。
Newborn neurons undergo inside-out migration to their final destinations during neocortical development. Reelin-induced tyrosine phosphorylation of disabled 1 (Dab1) is a critical mechanism controlling cortical neuron migration. However, the roles of Reelin-independent phosphorylation of Dab1 remain unclear. Here, we report that deleted in colorectal carcinoma (DCC) interacts with Dab1 via its P3 domain. Netrin 1, a DCC ligand, induces Dab1 phosphorylation at Y220 and Y232. Interestingly, knockdown of DCC or truncation of its P3 domain dramatically delays neuronal migration and impairs the multipolar-to-bipolar transition of migrating neurons. Notably, the migration delay and morphological transition defects are rescued by the expression of a phospho-mimetic Dab1 or a constitutively active form of Fyn proto-oncogene (Fyn), a member of the Src-family tyrosine kinases that effectively induces Dab1 phosphorylation. Collectively, these findings illustrate a DCC-Dab1 interaction that ensures proper neuronal migration during neocortical development.