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J. Biol. Chem., Vol. 282, Issue 24, 17877-17889, June 15, 2007

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Transcriptional Activators and Repressors for the Neuron-specific Expression of a Metabotropic Glutamate Receptor^*

Luca Crepaldi, Carmen Lackner, Corrado Corti, and Francesco Ferraguti¹

From the Department of Pharmacology, Innsbruck Medical University, Peter-Mayr-Strasse 1a, A-6020 Innsbruck, Austria and the Department of Biology, Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline Medicines Research Centre, 37135 Verona, Italy

Metabotropic glutamate receptor 1 (mGlu1) has a discrete distribution in the central nervous system restricted to neurons. Its expression undergoes important changes during development and in response to physiological and pathological modifications. Here, we have determined the structure of the mGlu1 gene and demonstrated that mGlu1 transcription takes places at alternative first exons. Moreover, we have identified active promoter regions upstream from the two most expressed first exons by means of luciferase reporter gene assays performed in primary cerebellar granule neurons. Targeted mutations of active elements constituting the core promoter and electrophoretic mobility shift assays demonstrated that the factors thyroid transcription factor-1 and CCAAT/enhancer-binding proteins act synergistically to promote mGlu1 transcription. We have also elucidated the molecular bases for the neuron-specific expression of mGlu1 identifying a neural restrictive silencing element and a regulatory factor for X box element, which suppressed mGlu1 expression in nonneuronal cells. These results reveal the molecular bases for cell- and context-specific expression of an important glutamate receptor critically involved in synaptogenesis, neuronal differentiation, synaptic transmission, and plasticity.

Received for publication, January 5, 2007 , and in revised form, April 3, 2007.

^* This work was supported by Austrian Science Foundation Fonds zur Förderung der wissenschaftlischen Forschung Grant P16720 [GenBank] (to F. F.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2 and Figs. 1 and 2.

¹ To whom correspondence should be addressed. Tel.: 43-512-9003-71204; Fax: 43-512-9003-72300; E-mail: francesco.ferraguti{at}i-med.ac.at.

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