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The Journal of Neuroscience, September 10, 2008, 28(37):9205-9217; doi:10.1523/JNEUROSCI.1897-08.2008

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Development/Plasticity/Repair
ClC3 Is a Critical Regulator of the Cell Cycle in Normal and Malignant Glial Cells

Christa W. Habela, Michelle L. Olsen, and Harald Sontheimer

Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294

Correspondence should be addressed to Harald Sontheimer, 1719 6th Avenue South, CIRC 425, Birmingham, AL 35294. Email: sontheimer{at}uab.edu

Although most brain cells are postmitotic, small populations of progenitor or stem cells can divide throughout life. These cells are believed to be the most likely source for primary brain malignancies including gliomas. Such tumors share many common features with nonmalignant glial cells but, because of their insidious growth, form cancers that are typically incurable. In studying the growth regulation of these tumors, we recently discovered that glioma cell division is preceded by a cytoplasmic condensation that we called premitotic condensation (PMC). PMC represents an obligatory step in cell replication and is linked to chromatin condensation. If perturbed, the time required to complete a division is significantly prolonged. We now show that PMC is a feature shared more commonly among normal and malignant cells and that the reduction of cell volume is accomplished by Cl^– efflux through ClC3 Cl^– channels. Patch-clamp electrophysiology demonstrated a significant upregulation of chloride currents at M phase of the cell cycle. Colocalization studies and coimmunoprecipitation experiments showed the channel on the plasma membrane and at the mitotic spindle. To demonstrate a mechanistic role for ClC3 in PMC, we knocked down ClC3 expression using short hairpin RNA constructs. This resulted in a significant reduction of chloride currents at M phase that was associated with a decrease in the rate of PMC and a similar impairment of DNA condensation. These data suggest that PMC is an integral part of cell division and is dependent on ClC3 channel function.

Key words: voltage-gated chloride channels; mitosis; glioma; tubulin; premitotic condensation; DNA condensation

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Received April 29, 2008; revised July 29, 2008; accepted Aug. 1, 2008.

Correspondence should be addressed to Harald Sontheimer, 1719 6th Avenue South, CIRC 425, Birmingham, AL 35294. Email: sontheimer{at}uab.edu

This article has been cited by other articles:

				W. Liang, J. B. Ray, J. Z. He, P. H. Backx, and M. E. Ward Regulation of Proliferation and Membrane Potential by Chloride Currents in Rat Pulmonary Artery Smooth Muscle Cells Hypertension, August 1, 2009; 54(2): 286 - 293. [Abstract] [Full Text] [PDF]

				C. W. Habela, N. J. Ernest, A. F. Swindall, and H. Sontheimer Chloride Accumulation Drives Volume Dynamics Underlying Cell Proliferation and Migration J Neurophysiol, February 1, 2009; 101(2): 750 - 757. [Abstract] [Full Text] [PDF]

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