Integrin-linked kinase is required for laminin-2-induced oligodendrocyte cell spreading and CNS myelination

J Cell Biol. 2003 Oct 27;163(2):397-408. doi: 10.1083/jcb.200304154.

Abstract

Early steps in myelination in the central nervous system (CNS) include a specialized and extreme form of cell spreading in which oligodendrocytes extend large lamellae that spiral around axons to form myelin. Recent studies have demonstrated that laminin-2 (LN-2; alpha2beta1gamma1) stimulates oligodendrocytes to extend elaborate membrane sheets in vitro (cell spreading), mediated by integrin alpha6beta1. Although a congenital LN-2 deficiency in humans is associated with CNS white matter changes, LN-2-deficient (dy/dy) mice have shown abnormalities primarily within the peripheral nervous system. Here, we demonstrate a critical role for LN-2 in CNS myelination by showing that dy/dy mice have quantitative and morphologic defects in CNS myelin. We have defined the molecular pathway through which LN-2 signals oligodendrocyte cell spreading by demonstrating requirements for phosphoinositide 3-kinase activity and integrin-linked kinase (ILK). Interaction of oligodendrocytes with LN-2 stimulates ILK activity. A dominant negative ILK inhibits LN-2-induced myelinlike membrane formation. A critical component of the myelination signaling cascade includes LN-2 and integrin signals through ILK.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Axons / physiology
  • Axons / ultrastructure
  • Cell Adhesion Molecules / metabolism
  • Cell Survival
  • Cells, Cultured
  • Central Nervous System / ultrastructure*
  • Cytoskeletal Proteins / metabolism
  • Enzyme Activation
  • Homozygote
  • Laminin / deficiency
  • Laminin / genetics
  • Laminin / metabolism*
  • Laminin / pharmacology
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Myelin Sheath / physiology*
  • Myelin Sheath / ultrastructure
  • Oligodendroglia / cytology
  • Oligodendroglia / enzymology
  • Oligodendroglia / physiology*
  • Optic Nerve / ultrastructure
  • Paxillin
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Cell Adhesion Molecules
  • Cytoskeletal Proteins
  • Laminin
  • Paxillin
  • Phosphoproteins
  • Pxn protein, mouse
  • Pxn protein, rat
  • Phosphatidylinositol 3-Kinases
  • integrin-linked kinase
  • Protein-Serine-Threonine Kinases