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The Journal of Neuroscience, July 27, 2005, 25(30):7022-7031; doi:10.1523/JNEUROSCI.1695-05.2005
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Development/Plasticity/Repair
Integrin-Linked Kinase Deletion from Mouse Cortex Results in Cortical Lamination Defects Resembling Cobblestone Lissencephaly
Agnieszka Niewmierzycka,1
Julia Mills,3
Rene St-Arnaud,4
Shoukat Dedhar,3 and
Louis F. Reichardt2
1Department of Pathology and 2Department of Physiology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143, 3British Columbia Cancer Research Centre and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada, V5Z 4E3, and 4Shriners Hospital and McGill University, Montreal, Quebec, Canada, H3G 1A6
Integrin-linked kinase (Ilk) is a scaffold and kinase that links integrin receptors to the actin cytoskeleton and to signaling pathways involved in cell adhesion, migration, and extracellular matrix deposition. Targeted deletion of Ilk from embryonic mouse dorsal forebrain neuroepithelium results in severe cortical lamination defects resembling cobblestone (type II) lissencephaly. Defects in adult mutants include neuronal invasion of the marginal zone, downward displacement of marginal zone components, fusion of the cerebral hemispheres, and scalloping of the dentate gyrus. These lesions are associated with abundant astrogliosis and widespread fragmentation of the basal lamina at the cortical surface. During cortical development, neuronal ectopias are associated with severe disorganization of radial glial processes and displacement of Cajal-Retzius cells. Lesions are not seen when Ilk is specifically deleted from embryonic neurons. Interestingly, targeted Ilk deletion has no effect on proliferation or survival of cortical cells or on phosphorylation of two Ilk substrates, Pkb/Akt and Gsk-3 , suggesting that Ilk does not regulate cortical lamination via these enzymes. Instead, Ilk acts in vivo as a major intracellular mediator of integrin-dependent basal lamina formation. This study demonstrates a critical role for Ilk in cortical lamination and suggests that Ilk-associated pathways are involved in the pathogenesis of cobblestone lissencephalies.
Key words: integrin-linked kinase; extracellular matrix; cortical development; cobblestone lissencephaly; radial glia; reelin
Received April 28, 2005;
revised June 14, 2005;
accepted June 16, 2005.
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