Human Molecular Genetics Advance Access originally published online on June 28, 2007
Human Molecular Genetics 2007 16(17):2122-2134; doi:10.1093/hmg/ddm162
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Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1
1 UCL Institute of Child Health and 2 UCL Institute of Neurology, University College London, UK, 3 National Institute for Medical Research, London, UK and 4 Service de Neurologie, Universite Libre de Bruxelles, Hopital Erasme, Brussels, Belgium
* To whom correspondence should be addressed at:, Institut de Neuropatologia, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Vía s/n Km 2.7, 08907 Hospitalet del Llobregat, Barcelona, Spain. Tel: +34 932607411; Fax: +34 932607782; E-mail: amatilla{at}idibell.org
Received May 10, 2007; Revised May 30, 2007; Accepted June 21, 2007
Ataxin 1 (Atxn1) is a protein of unknown function associated with spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease of late onset with variable degrees of cerebellar ataxia, ophthalmoplegia and neuropathy. SCA1 is caused by the toxic effects triggered by an expanded polyglutamine (polyQ) within Atxn1 resulting in neurodegeneration in the cerebellum, brain stem and spinocerebellar tracts. To gain insights into Atxn1 function, we have analysed the cerebellar gene expression profiles by microarray analysis in Atxn1-null mice, and identified alterations in expression of genes regulated by Sp1-dependent transcription, including the dopamine receptor D2 (Drd2), retinoic acid/thyroid hormone and Wnt-signalling. Interestingly, Drd2 expression levels are reduced in both Atxn1-null and transgenic mice expressing a pathogenic human Atxn1 with an expanded polyglutamine in cerebellar Purkinje cells. Our co-transfection experiments in human neuroblastoma SH-SY5Y cells and luciferase assays provide evidence for transcriptional regulation of Drd2 by Atxn1 and its AXH module. We show that Atxn1 occupies at the Drd2 promoter in vivo, and interacts and functions synergistically with the zinc-finger transcription factor Sp1 to co-regulate Drd2 expression. The interaction and transcriptional effects are mediated by the AXH domain within Atxn1 and are abrogated by the expanded polyQ within Atxn1. Therefore, this study identifies novel molecular targets that are regulated by Atxn1 which might contribute to the motor deficits in SCA1, and provides new insights into the mechanisms by which Atxn1 co-regulates transcription.