Human Molecular Genetics Advance Access published online on June 28, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm162
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Down-regulation of the Dopamine Receptor D2 in mice lacking Ataxin 1
1 UCL Institute of Child Health, University College London, London, United Kingdom 2 UCL Institute of Neurology, University College London, United Kingdom 3 National Institute for Medical Research, London, United Kingdom 4 Service de Neurologie, Universite Libre de Bruxelles - Hopital Erasme, Brussels, Belgium
* Correspondence to: Antoni Matilla Dueñas, BSc MB DSc Institut de Neuropatologia, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Vía s/n Km 2.7, 08907 Hospitalet del Llobregat, Barcelona, Spain. Tel.: +34-93-2607411 Fax: +34-93-2607782, 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 ataxin 1 function, we have analyzed 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 ataxin 1 which might contribute to the motor deficits in SCA1, and provides new insights into the mechanisms by which Atxn1 co-regulates transcription.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. G. Shah, M. J. Friedman, S. Huang, M. Roberts, X.-J. Li, and S. Li Transcriptional dysregulation of TrkA associates with neurodegeneration in spinocerebellar ataxia type 17 Hum. Mol. Genet., November 1, 2009; 18(21): 4141 - 4152. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Benn, T. Sun, G. Sadri-Vakili, K. N. McFarland, D. P. DiRocco, G. J. Yohrling, T. W. Clark, B. Bouzou, and J.-H. J. Cha Huntingtin Modulates Transcription, Occupies Gene Promoters In Vivo, and Binds Directly to DNA in a Polyglutamine-Dependent Manner J. Neurosci., October 15, 2008; 28(42): 10720 - 10733. [Abstract] [Full Text] [PDF]
|
|