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The Journal of Neuroscience, September 24, 2003, 23(25):8673-8681

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Development/Plasticity/Repair
Disregulated RhoGTPases and Actin Cytoskeleton Contribute to the Migration Defect in Lis1-Deficient Neurons

Stanislav S. Kholmanskikh,^1,2 Joseph S. Dobrin,¹ Anthony Wynshaw-Boris,³ Paul C. Letourneau,^2 * and M. Elizabeth Ross^1,2 *

Departments of ¹Neurology and ²Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and ³Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California 92093

Lissencephaly is a severe brain malformation caused by impaired neuronal migration. Lis1, a causative gene, functions in an evolutionarily conserved nuclear translocation pathway regulating dynein motor and microtubule dynamics. Whereas microtubule contributions to neuronal motility are incompletely understood, the actin cytoskeleton is essential for crawling cell movement of all cell types investigated. Lis1 haploinsufficiency is shown here to also result in reduced filamentous actin at the leading edge of migrating neurons, associated with upregulation of RhoA and downregulation of Rac1 and Cdc42 activity. Disruption of RhoA function through pharmacological inhibition of its effector kinase, p160ROCK, restores normal Rac1 and Cdc42 activity and rescues the motility defect in Lis1+/- neurons. These data indicate a previously unrecognized role for Lis1 protein in neuronal motility by promoting actin polymerization through the regulation of Rho GTPase activity. This effect of Lis1 on GTPases does not appear to occur through direct Lis1 binding of Rho, but could involve Lis1 effects on Rho modulatory proteins or on microtubule dynamics.

Key words: Lis1; platelet activating factor acetyl hydrolase 1b1 (Pafah1b1); neuronal migration; cerebellar granule neurons; RhoA; Rac1; Cdc42

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Received April 22, 2003; revised July 10, 2003; accepted August 6, 2003.

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