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First published on March 8, 2005; DOI: 10.1124/mol.104.010751

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Received for publication December 27, 2004.
Revised March 7, 2005.
Accepted for publication March 8, 2005.

NRSF regulates the N-Methyl-D-aspartate receptor 2B subunit gene in basal and ethanol-induced gene expression in fetal cortical neurons

Mei Qiang 1*, Sheela Rani Kadapakkam 1, Maharaj K. Ticku 1

1 The University of Texas Health Science Center at San Antonio

* Address correspondence to: E-mail: qiang{at}uthscsa.edu

Abstract

Neuron-restrictive silencer factor (NRSF) is a transcriptional repressor of multiple neuronal genes. This study addressed the role of NRSF in NMDA receptor NR2B promoter activity and the molecular mechanisms of ethanol-induced NR2B up-regulation in fetal cortical neurons. The 5'-flanking region of the NR2B gene contains five NRSE-like elements. Functional analysis of the upstream regions of the NR2B gene by transient transfection of neurons revealed that neuron-restrictive silencer element (NRSE) motifs located between bp -1407 and -2741 represses transcription of the gene. Analysis by EMSA and reporter gene assay identified NRSE2 and 3 as responsible for repressing NR2B gene transcription. The identity of NRSF as the functional binding factor is suggested by the specific binding of in vitro synthesized NRSF or cell lysate to the labeled probes and the specific antibody-induced supershift. Furthermore, whereas mutations of NRSE2 and 3 motifs increased the promoter activity, overexpression of NRSF reduced it significantly. The pattern of NRSF expression during development was investigated, and demonstrated that the highest expression is on E14 with moderate expression on P0, reflecting a possible role of NRSF as a regulator during development. Treatment of cultured cortical neurons with 100 mM ethanol for 5 days caused a significant decrease in the NRSF mRNA and protein levels, NRSF/NRSE binding activity, and an increase in the promoter activity. Therefore, our studies suggest that NRSF is a negative regulator of NR2B expression and may contribute to the ethanol-induced up-regulation of the NR2B gene in fetal cortical neurons.


Key words: Glutamate, DNA binding sites, Promoter analysis, Regulation of gene expression, Regulation - transcriptional, Alcohol


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