Journal
JOURNAL OF NEUROSCIENCE
Volume 28, Issue 48, Pages 13008-13013Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2363-08.2008
Keywords
neuronal migration; DCX; MARK2/Par-1; lissencephaly; microtubules; in utero electroporation
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Funding
- Israeli Science Foundation [270/04]
- Foundation Jerome Lejeune
- Federal German Ministry for Education and Research
- German-Israeli collaboration Grant [Gr-1905]
- March of Dimes
- Paul Godfrey Research Foundation in Childrens' Diseases
- Benoziyo Center for Neurological Diseases
- Kekst Center
- Forcheimer Center
- Weizmann-Pasteur collaborative grant
- Michigan Women of Wisdom Fund
- Jewish communal fund
- Albert Einstein College of Medicine of Yeshiva University
- David and Fela Shapell Family Center for Genetic Disorders Research
- Deutsche Forschungsgemeinschaft
- Max-Planck-Gesellschaft
- [6-FY07-388]
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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.
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