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The Journal of Neuroscience, January 7, 2009, 29(1):288-299; doi:10.1523/JNEUROSCI.2934-08.2009

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

Xuejun Chai,¹ Eckart Förster,^1,3 Shanting Zhao,¹ Hans H. Bock,² and Michael Frotscher^1,2

¹Institut für Anatomie und Zellbiologie and ²Zentrum für Neurowissenschaften, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany, and ³Institut für Anatomie I: Zelluläre Neurobiologie, Universität Hamburg, D-20246 Hamburg, Germany

Correspondence should be addressed to Michael Frotscher, Institut für Anatomie und Zellbiologie, Albertstrasse 17, D-79104 Freiburg, Germany. Email: Michael.Frotscher{at}anat.uni-freiburg.de

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.

Key words: radial migration; Reelin signaling; cortical lamination; actin cytoskeleton; cofilin; reeler mutant

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Received June 25, 2008; revised Oct. 8, 2008; accepted Nov. 25, 2008.

Correspondence should be addressed to Michael Frotscher, Institut für Anatomie und Zellbiologie, Albertstrasse 17, D-79104 Freiburg, Germany. Email: Michael.Frotscher{at}anat.uni-freiburg.de

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