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The Journal of Neuroscience, November 26, 2008, 28(48):13008-13013; doi:10.1523/JNEUROSCI.2363-08.2008

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Brief Communications
Antagonistic Effects of Doublecortin and MARK2/Par-1 in the Developing Cerebral Cortex

Tamar Sapir,¹ Anat Shmueli,¹ Talia Levy,¹ Thomas Timm,³ Michael Elbaum,² Eva-Maria Mandelkow,³ and Orly Reiner¹

Departments of ¹Molecular Genetics and ²Materials and Interfaces, The Weizmann Institute of Science, 76100 Rehovot, Israel, and ³Max 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, 76100 Rehovot, Israel. Email: orly.reiner{at}weizmann.ac.il

Abnormal neuronal migration is manifested in brain malformations such as lissencephaly. The impairment in coordinated cell motility likely reflects a faulty mechanism of cell polarization or coupling between polarization and movement. Here we report on the relationship between the polarity kinase MARK2/Par-1 and its substrate, the well-known lissencephaly-associated gene doublecortin (DCX), during cortical radial migration. We have previously shown using in utero electroporation that reduced MARK2 levels resulted in multipolar neurons stalled at the intermediate zone border, similar to the phenotype observed in the case of DCX silencing. However, whereas reduced MARK2 stabilized microtubules, we show here that knock-down of DCX increased microtubule dynamics. This led to the hypothesis that simultaneous reduction may alleviate the phenotype. Coreduction of MARK2 and DCX resulted in a partial restoration of the normal neuronal migration phenotype in vivo. The kinetic behavior of the centrosomes reflected the different molecular mechanisms activated when either protein was reduced. In the case of reducing MARK2 processive motility of the centrosome was hindered, whereas when DCX was reduced, centrosomes moved quickly but bidirectionally. Our results stress the necessity for successful coupling between the polarity pathway and cytoplasmic dynein-dependent activities for proper neuronal migration.

Key words: neuronal migration; DCX; MARK2/Par-1; lissencephaly; microtubules; in utero electroporation

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Received May 26, 2008; revised Sept. 27, 2008; accepted Oct. 22, 2008.

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

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