Integrin-linked kinase is required for laminin-2-induced oligodendrocyte cell spreading and CNS myelination.
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.
Department of Neurology, Beth Israel Deaconess Medical Center, Center for Neurodegeneration and Repair and the Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Soo Jin
SJ
Chun
Matthew N
MN
Rasband
Richard L
RL
Sidman
Amyn A
AA
Habib
Timothy
T
Vartanian
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002490:Central Nervous System / Q000648:ultrastructure*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006720:Homozygote; D007797:Laminin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D009900:Optic Nerve / Q000648:ultrastructure; D051419:Paxillin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099200:Scaffold Protein ILK
D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D007797:Laminin; D051419:Paxillin; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C496062:Pxn protein, mouse; C496063:Pxn protein, rat