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J. Biol. Chem., Vol. 280, Issue 16, 16284-16294, April 22, 2005

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Stage-specific Expression of Myelin Basic Protein in Oligodendrocytes Involves Nkx2.2-mediated Repression That Is Relieved by the Sp1 Transcription Factor^*

Qiou Wei, W. Keith Miskimins, and Robin Miskimins

From the Division of Basic Biomedical Sciences, University of South Dakota School of Medicine, Vermillion, South Dakota 57069

The homeodomain-containing protein Nkx2.2 is critical for the development of oligodendrocyte lineage cells, but the target genes of Nkx2.2 regulation have not been identified. In the present study, we found that the myelin basic protein gene is one of the genes that is regulated by Nkx2.2. Expression of Nkx2.2 represses the expression of myelin basic protein in oligodendrocyte progenitors. Two regulatory elements in the myelin basic protein promoter were identified and found to interact with Nkx2.2 in vitro. Despite their sequence divergence, both sites were involved in the Nkx2.2-mediated repression of the myelin basic protein promoter. Binding of Nkx2.2 also blocked and disrupted the binding of the transcriptional activator Pur to the myelin basic protein promoter. Additionally Nkx2.2 recruited a histone deacetylase 1-mSin3A complex to the myelin basic protein promoter. We also found that the transcription factor Sp1 was able to compete off the binding of Nkx2.2 to its consensus binding site in vitro and reversed the repressive effect of Nkx2.2 in vivo. Our data revealed a novel role for Nkx2.2 in preventing the precocious expression of myelin basic protein in immature oligodendrocytes. Based on this study and our previous reports, a model for myelin basic protein gene control is proposed.

Received for publication, January 14, 2005 , and in revised form, February 2, 2005.

^* This work was supported by National Multiple Sclerosis Society Grant RG2079-D-6. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Grant 5-P20 RR16479–04 (South Dakota Biomedical Research Infrastructure Network/IDeA Network of Biomedical Research Excellence) from the Institutional Development Award Program of the National Center for Research Resources.

To whom correspondence should be addressed: Division of Basic Biomedical Sciences, University of South Dakota School of Medicine, 414 E. Clark St., Vermillion, SD 57069. Tel.: 605-677-5131; Fax: 605-677-6381; E-mail: rmiskim{at}usd.edu.

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