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The Journal of Neuroscience, May 28, 2008, 28(22):5710-5720; doi:10.1523/JNEUROSCI.0911-08.2008

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Neurobiology of Disease
Accurate Balance of the Polarity Kinase MARK2/Par-1 Is Required for Proper Cortical Neuronal Migration

Tamar Sapir,¹ Sivan Sapoznik,¹ Talia Levy,¹ Danit Finkelshtein,¹ Anat Shmueli,¹ Thomas Timm,² Eva-Maria Mandelkow,² and Orly Reiner¹

¹Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel, and ²Max Planck Unit for Structural Molecular Biology, 22607 Hamburg, Germany

Correspondence should be addressed to Orly Reiner, Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. Email: orly.reiner{at}weizmann.ac.il

Radial neuronal migration is key in structuring the layered cortex. Here we studied the role of MARK2/Par-1 in this process. The dual name stands for the MAP/microtubule affinity-regulating kinase 2 (MARK2) and the known polarity kinase 1 (Par-1). Reduced MARK2 levels using in utero electroporation resulted in multipolar neurons stalled at the intermediate zone border. Reintroduction of the wild-type kinase postmitotically improved neuronal migration. Our results indicated that reduction in MARK2 affected centrosomal dynamics in migrating neurons of the cerebral cortex. Increased MARK2 has been shown to destabilize microtubules, and here we show for the first time that reduced MARK2 stabilized microtubules in primary cultured neurons. Kinase-independent activity permitted multipolar-to-bipolar transition but did not restore proper migration. Increased MARK2 levels resulted in a different phenotype, which is loss of neuronal polarity. MARK2 kinase activity reduction hindered migration in the developing brain, which was rescued by increasing kinase activity. Our results stress the necessity of maintaining dynamic microtubules for proper neuronal migration. Furthermore, the exact requirements for MARK2 and its kinase activity vary during the course of neuronal migration. Collectively, our results stress the requirements for the different roles of MARK2 during neuronal migration.

Key words: neuronal migration; mental retardation; MARK2/Par-1; polarity kinase; microtubules; in utero electroporation

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Received Feb. 29, 2008; revised April 8, 2008; accepted April 20, 2008.

Correspondence should be addressed to Orly Reiner, Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. Email: orly.reiner{at}weizmann.ac.il

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