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The Journal of Neuroscience, January 18, 2006, 26(3):830-840; doi:10.1523/JNEUROSCI.1852-05.2006

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Development/Plasticity/Repair
Critical Role of Integrin-Linked Kinase in Granule Cell Precursor Proliferation and Cerebellar Development

Julia Mills,¹ Agnieszka Niewmierzycka,⁴ Arusha Oloumi,¹ Beatriz Rico,⁵ Rene St-Arnaud,⁶ Ian R. Mackenzie,² Nasrin M. Mawji,¹ Jason Wilson,³ Louis F. Reichardt,⁵ and Shoukat Dedhar¹

Departments of ¹Biochemistry and Molecular Biology, ²Pathology, and ³Ophthalmology, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z4, ⁴Department of Pathology and ⁵Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California 94143, and ⁶Shriners Hospital and McGill University, Montreal, Quebec, Canada H3A 2T5

Integrin-linked kinase (ILK) is a serine/threonine protein kinase that plays an important role in integrin signaling and cell proliferation. We used Cre recombinase (Cre)-loxP technology to study CNS restricted knock-out of the ilk gene by either Nestin-driven or gfap-driven Cre-mediated recombination. Developmental changes in ilk-excised brain regions are similar to those observed in mice lacking the integrin 1 subunit in the CNS, including defective laminin deposition, abnormal glial morphology, and alterations in granule cell migration. Decreases in 6-bromodeoxyuridine (BrdU) pulse labeling and proliferating cell nuclear antigen expression in the external granule cell layer of the cerebellum demonstrated that proliferation is disrupted in granule cells lacking ILK. Previous studies have shown that laminin-sonic hedgehog (Shh)-induced granule cell precursor (GCP) proliferation is dependent on 1 integrins, several of which bind laminin and interact with ILK through the 1 cytoplasmic domain. Both ex vivo deletion of ilk and a small molecule inhibitor of ILK kinase activity decreased laminin-Shh-induced BrdU labeling in cultured GCPs. Together, these results implicate ILK as a critical effector in a signaling pathway necessary for granule cell proliferation and cerebellar development.

Key words: granule cell precursor; integrin; integrin-linked kinase; laminin; proliferation; sonic hedgehog

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Received May 9, 2005; revised November 23, 2005; accepted November 25, 2005.

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