Reelin controls neuronal positioning by promoting cell-matrix adhesion via inside-out activation of integrin α5β1

Neuron. 2012 Oct 18;76(2):353-69. doi: 10.1016/j.neuron.2012.07.020. Epub 2012 Oct 17.

Abstract

Birthdate-dependent neuronal layering is fundamental to neocortical functions. The extracellular protein Reelin is essential for the establishment of the eventual neuronal alignments. Although this Reelin-dependent neuronal layering is mainly established by the final neuronal migration step called "terminal translocation" beneath the marginal zone (MZ), the molecular mechanism underlying the control by Reelin of terminal translocation and layer formation is largely unknown. Here, we show that after Reelin binds to its receptors, it activates integrin α5β1 through the intracellular Dab1-Crk/CrkL-C3G-Rap1 pathway. This intracellular pathway is required for terminal translocation and the activation of Reelin signaling promotes neuronal adhesion to fibronectin through integrin α5β1. Since fibronectin is localized in the MZ, the activated integrin α5β1 then controls terminal translocation, which mediates proper neuronal alignments in the mature cortex. These data indicate that Reelin-dependent activation of neuronal adhesion to the extracellular matrix is crucial for the eventual birth-date-dependent layering of the neocortex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Analysis of Variance
  • Animals
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • Cell Adhesion / physiology*
  • Cell Adhesion Molecules, Neuronal / drug effects
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cell Line, Transformed
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Movement / physiology*
  • Electroporation
  • Embryo, Mammalian
  • Extracellular Matrix Proteins / drug effects
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • Green Fluorescent Proteins / genetics
  • Humans
  • Integrin alpha5beta1 / genetics
  • Integrin alpha5beta1 / metabolism*
  • Mice
  • Mice, Inbred ICR
  • Mice, Neurologic Mutants
  • Mice, Transgenic
  • Mutation / genetics
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / drug effects
  • Neurons / physiology*
  • Nuclear Proteins
  • Pregnancy
  • Proto-Oncogene Proteins c-crk / metabolism
  • Serine Endopeptidases / drug effects
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Somatosensory Cortex / cytology
  • rap1 GTP-Binding Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CRKL protein
  • Cell Adhesion Molecules, Neuronal
  • Dab1 protein, mouse
  • Extracellular Matrix Proteins
  • Integrin alpha5beta1
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-crk
  • Green Fluorescent Proteins
  • Serine Endopeptidases
  • reelin protein
  • rap1 GTP-Binding Proteins