Reelin stabilizes the actin cytoskeleton of neuronal processes by inducing n-cofilin phosphorylation at serine3.
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.
Chai
Xuejun
X
Institut für Anatomie und Zellbiologie, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany.
Förster
Eckart
E
Zhao
Shanting
S
Bock
Hans H
HH
Frotscher
Michael
M
D000199:Actins / Q000378:metabolism*; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000494:pharmacology / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects; D051338:Cofilin 1 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D026502:LDL-Receptor Related Proteins; D054461:Lim Kinases / Q000378:metabolism; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency; D018110:Receptors, Lipoprotein / Q000172:deficiency; D000091042:Reelin Protein; D012694:Serine / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000494:pharmacology / Q000502:physiology*; D013347:Subcellular Fractions / Q000187:drug effects; D014162:Transfection / Q000379:methods; D019061:src-Family Kinases / Q000378:metabolism
D000199:Actins; D015816:Cell Adhesion Molecules, Neuronal; D051338:Cofilin 1; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D054461:Lim Kinases; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D000091042:Reelin Protein; D012694:Serine; D012697:Serine Endopeptidases; D019061:src-Family Kinases; C103773:Dab1 protein, mouse; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C469363:reelin receptor; C515893:Limk1 protein, mouse; C000717127:RELN protein, human; C000717128:Reln protein, mouse