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The Journal of Neuroscience, June 6, 2007, 27(23):6185-6196; doi:10.1523/JNEUROSCI.0628-07.2007

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Cellular/Molecular
A Crucial Role for p57^Kip2 in the Intracellular Timer that Controls Oligodendrocyte Differentiation

Jason C. Dugas, Adiljan Ibrahim, and Ben A. Barres

Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305-5125

Correspondence should be addressed to Dr. Jason C. Dugas, Stanford University School of Medicine, Department of Neurobiology, Fairchild Building, Room D205, 299 Campus Drive, Stanford, CA 94305-5125. Email: jcdugas{at}alum.mit.edu

The intracellular molecular mechanism that controls the timing of oligodendrocyte differentiation remains unknown. Temple and Raff (1986) previously showed that an oligodendrocyte precursor cell (OPC) can divide a maximum of approximately eight times before its daughter cells simultaneously cease proliferating and differentiate into oligodendrocytes. They postulated that over time the level of an intracellular molecule might synchronously change in each daughter cell, ultimately reaching a level that prohibited additional proliferation. Here, we report the discovery of such a molecule, the cyclin-dependent kinase inhibitor p57^Kip2 (Cdkn1c). We show in vitro that all daughters of a clone of OPCs express similar levels of p57^Kip2, that p57^Kip2 levels increase over time in proliferating OPCs, and that p57^Kip2 levels regulate how many times an OPC can divide before differentiating. These findings reveal a novel part of the mechanism by which OPCs measure time and are likely to extend to similar timers in many other precursor cell types.

Key words: oligodendrocyte; p57Kip2; CDKN1C; myelin; multiple sclerosis; ZFP536; Id4

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Received Feb. 12, 2007; revised April 30, 2007; accepted May 1, 2007.

Correspondence should be addressed to Dr. Jason C. Dugas, Stanford University School of Medicine, Department of Neurobiology, Fairchild Building, Room D205, 299 Campus Drive, Stanford, CA 94305-5125. Email: jcdugas{at}alum.mit.edu

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