Integrin-linked kinase deletion from mouse cortex results in cortical lamination defects resembling cobblestone lissencephaly.

Abstract

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-3beta, 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.

• Authors: Agnieszka Niewmierzycka, Julia Mills, Rene St-Arnaud, Shoukat Dedhar, Louis F Reichardt
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 25 Issue 30 Pg. 7022-31 (Jul 27 2005) ISSN: 1529-2401 [Electronic] United States
• PMID: 16049178 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• integrin-linked kinase
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Animals
• Cell Division (physiology)
• Cell Survival (physiology)
• Cerebral Cortex (abnormalities, pathology, physiology)
• Extracellular Matrix (enzymology)
• Gene Deletion
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Mice
• Mice, Knockout
• Neuroglia (pathology)
• Neurons (cytology, physiology)
• Phosphorylation
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)