CLASP2 Links Reelin to the Cytoskeleton during Neocortical Development.
CLASP2 Links Reelin to the Cytoskeleton during Neocortical Development.
复制标题
DOI：
10.1016/j.neuron.2017.02.039
复制
发表时间：
2017-03-22
期刊：
影响因子：
16.2
通讯作者：
Ho A
中科院分区：
文献类型：
--
作者：
Dillon GM;Tyler WA;Omuro KC;Kambouris J;Tyminski C;Henry S;Haydar TF;Beffert U;Ho A
Reelin信号通路在调节新皮质发育中起着至关重要的作用。然而，人们对Reelin在神经元迁移过程中如何控制细胞骨架知之甚少。在这里，我们确定CLASP2是Reelin信号通路中一个关键的细胞骨架效应因子。我们证明CLASP2在新皮质发育过程中有不同的作用，调节神经元的产生和控制神经元的迁移、极性和形态发生。我们发现，在迁移的神经元中CLASP2的下调导致更深皮质层的细胞定位错误，中心体-高尔基复合体的位置异常，以及前导突起的异常长度/方向。我们发现，Reelin在带正电的丝氨酸/精氨酸富集区调节着几个磷酸化位点，这些位点构成了CLASP2一致的GSK3β磷酸化基序。此外，CLASP2的磷酸化调节其与Reelin接头Dab1的相互作用，这种联系是CLASP2影响轴突延伸和运动所必需的。综上所述，我们的数据显示，CLASP2是大脑发育过程中协调细胞骨架动力学的重要Reelin效应器。
The Reelin signaling pathway plays a crucial role in regulating neocortical development. However, little is known about how Reelin controls the cytoskeleton during neuronal migration. Here, we identify CLASP2 as a key cytoskeletal effector in the Reelin signaling pathway. We demonstrate that CLASP2 has distinct roles during neocortical development regulating neuron production and controlling neuron migration, polarity, and morphogenesis. We found down-regulation of CLASP2 in migrating neurons leads to mislocalized cells in deeper cortical layers, abnormal positioning of the centrosome-Golgi complex, and aberrant length/orientation of the leading process. We discovered Reelin regulates several phosphorylation sites within the positively-charged serine/arginine rich region that constitute consensus GSK3β phosphorylation motifs of CLASP2. Furthermore, phosphorylation of CLASP2 regulates its interaction with the Reelin adaptor Dab1 and this association is required for CLASP2 effects on neurite extension and motility. Together, our data reveal CLASP2 is an essential Reelin effector orchestrating cytoskeleton dynamics during brain development.