Reelin Stabilizes the Actin Cytoskeleton of Neuronal Processes by Inducing n-Cofilin Phosphorylation at Serine3

被引:166
作者
Chai, Xuejun [1 ]
Foerster, Eckart [1 ,3 ]
Zhao, Shanting [1 ]
Bock, Hans H. [2 ]
Frotscher, Michael [1 ,2 ]
机构
[1] Univ Freiburg, Inst Anat & Zellbiol, D-79104 Freiburg, Germany
[2] Univ Freiburg, Zentrum Neurowissensch, D-79104 Freiburg, Germany
[3] Univ Hamburg, Inst Anat Zellulare Neurobiol 1, D-20246 Hamburg, Germany
关键词
radial migration; Reelin signaling; cortical lamination; actin cytoskeleton; cofilin; reeler mutant; DEVELOPING CEREBRAL-CORTEX; RADIAL GLIAL SCAFFOLD; APOE RECEPTOR 2; CORTICAL DEVELOPMENT; BRAIN-DEVELOPMENT; CELL-MIGRATION; DENTATE GYRUS; PHOSPHATIDYLINOSITOL; 3-KINASE; TYROSINE KINASE; CAJAL-RETZIUS;
D O I
10.1523/JNEUROSCI.2934-08.2009
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The extracellular matrix protein Reelin, secreted by Cajal-Retzius cells in the marginal zone of the cortex, controls the radial migration of cortical neurons. Reelin signaling involves the lipoprotein receptors apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR), the adapter protein Disabled1 (Dab1), and phosphatidylinositol-3-kinase (PI3K). Eventually, Reelin signaling acts on the cytoskeleton; however, these effects on cytoskeletal organization have remained elusive. In Reelin-deficient mutant mice, most cortical neurons are unable to migrate to their destinations, suggesting a role for Reelin signaling in the dynamic cytoskeletal reorganization that is required for neurons to migrate. Here, we show that Reelin signaling leads to serine3 phosphorylation of n-cofilin, an actin-depolymerizing protein that promotes the disassembly of F-actin. Phosphorylation at serine3 renders n-cofilin unable to depolymerize F-actin, thereby stabilizing the cytoskeleton. We provide evidence for ApoER2, Dab1, Src family kinases (SFKs), and PI3K to be involved in n-cofilin serine3 phosphorylation. Phosphorylation of n-cofilin takes place in the leading processes of migrating neurons as they approach the Reelin-containing marginal zone. Immunostaining for phospho-cofilin in dissociated reeler neurons is significantly increased after incubation in Reelin-containing medium compared with control medium. In a stripe choice assay, neuronal processes are stable on Reelin-coated stripes but grow on control stripes by forming lamellipodia. These novel findings suggest that Reelin-induced stabilization of neuronal processes anchors them to the marginal zone which appears to be required for the directional migration process.
引用
收藏
页码:288 / 299
页数:12
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