Published 27 October 2003. doi:10.1083/jcb.200304154
© The Rockefeller University Press,
0021-9525/2003/10/397 $8.00
The Journal of Cell Biology, Volume 163, Number 2, 397-408
Integrin-linked kinase is required for laminin-2–induced oligodendrocyte cell spreading and CNS myelination
Soo Jin Chun1,
Matthew N. Rasband2,
Richard L. Sidman1,
Amyn A. Habib1 and
Timothy Vartanian1
1 Department of Neurology, Beth Israel Deaconess Medical Center, Center for Neurodegeneration and Repair and the Program in Neuroscience, Harvard Medical School, Boston, MA 02115
2 Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030
Address correspondence to Timothy Vartanian, Dept. of Neurology, Beth Israel Deaconess Medical Center, Center for Neurodegeneration and Repair and the Program in Neuroscience, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: (617) 667-0805. Fax: (617) 667-0836. email: tvartani{at}caregroup.harvard.edu
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; 
2ß1
1) stimulates oligodendrocytes to extend elaborate membrane sheets in vitro (cell spreading), mediated by integrin 6ß1. 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.
Key Words: dy/dy mice; LN-2; ILK; PI3K; focal adhesion
Abbreviations used in this paper: CC, corpus callosum; CNS, central nervous system; DN, dominant negative; FA, focal adhesion; H&E, hematoxylin and eosin; ILK, integrin-linked kinase; LN-2, laminin-2; MBP, myelin basic protein; MOI, multiplicity of infection; O1, mAb to galactocerebroside; ON, optic nerve; OPC, oligodendrocyte precursor cell; P, postnatal; PI3K, phosphoinositide 3-kinase; PLO, poly-L-ornithine; PNS, peripheral nervous system; SC, spinal cord; SN, sciatic nerve; TN-C, tenascin-C; TRE, tetracycline responsive promoter; TSP-1, thrombospondin-1.
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