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Originally published In Press as doi:10.1074/jbc.C100758200 on January 24, 2002

J. Biol. Chem., Vol. 277, Issue 11, 8763-8766, March 15, 2002
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ACCELERATED PUBLICATION
Blocking HES1 Expression Initiates GABAergic Differentiation and Induces the Expression of p21CIP1/WAF1 in Human Neural Stem Cells*

Peter KabosDagger , Andrea Kabosova, and Toomas Neuman

From the Department of Surgery, The CSMC Burns & Allen Research Institute, Cedars Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048

Mammalian neural stem cells can develop into a variety of neuronal and glial cell types. This involves a highly coordinated process of differentiation in which the Notch signaling pathway and the system of helix-loop-helix (HLH) transcriptional regulators play a key role. By exercising control over proliferation, initiation of differentiation, neurite outgrowth, and synaptogenesis, the network of HLH transcription factors regulates the fate of neural stem cells and progenitors. Here we show that the HLH transcription factor HES1 regulates the proliferation of human neural stem cells and that blocking its expression stimulates the expression of cyclin-dependent kinase inhibitor p21CIP1/WAF1. Furthermore, we demonstrate that the suppression of HES1 expression initiates differentiation of neural stem cells into neurons, the majority of which develop the GABAergic phenotype. These findings underscore the importance of the HLH network, and HES1 in particular, in guiding the phenotypic development of neural stem cells.

* This work was supported by grants from the Spinal Cord Society and CeMines, LLC (to T. N.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Maxine Dunitz Neurosurgical Inst., Cedars-Sinai Medical Center, 110 George Burns Rd., Davis Rm. 2096, Los Angeles, CA 90048. E-mail: kabosp@cshs.org.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.