Human Molecular Genetics Advance Access published online on November 12, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddh005
© 2003 by Oxford University Press
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1 Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8096, St. Louis, MO 63110; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110
* To whom correspondence should be addressed. E-mail: chen{at}vision.wustl.edu.
Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder caused by expansion of a polyglutamine tract in the ataxin-7 protein. A unique feature of SCA7 is degeneration of photoreceptor cells in the retina, resulting in cone-rod dystrophy. In a SCA7 transgenic mouse model that we developed, we found that the cone-rod dystrophy involves altered photoreceptor gene expression due to interference with Crx, a homeodomain transcription factor containing a glutamine-rich region. To determine the basis of the Crx-ataxin-7 interaction, we generated Crx and ataxin-7 truncation and point mutants, and tested the ability of mutant versions of either protein to co-immunoprecipitate the normal version of the other protein. We thus localized Crx's ataxin-7 interaction domain to its glutamine-rich region and mapped ataxin-7's Crx binding domain to its glutamine tract. We confirmed the importance of each protein's respective glutamine region for a productive interaction by performing Crx transactivation assays in HEK293 cells and correlating the extent of Crx transcription interference with the intactness of each protein's glutamine region. We also established that ataxin-7 must localize to the nucleus to repress Crx transactivation, and mapped the likely nuclear localization signals to ataxin-7's carboxy-terminal region. Finally, using chromatin immunoprecipitation, we demonstrated that Crx and ataxin-7 engage in a functionally significant interaction by co-occupying the promoter and enhancer regions of Crx-regulated retinal genes in vivo. Our results suggest that one mechanism of SCA7 disease pathogenesis is transcription dysregulation, and that Crx transcription interference is a predominant factor in SCA7 cone-rod dystrophy retinal degeneration.
Article
Interference of Crx-dependent transcription by ataxin-7 involves interaction between the glutamine regions and requires the ataxin-7 carboxy-terminal region for nuclear localization
2 Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110
3 Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD
4 Department of Laboratory Medicine, University of Washington Medical Center, Seattle, Washington 98195
5 Department of Laboratory Medicine, University of Washington Medical Center, Seattle, Washington 98195; Department of Medicine (Division of Medical Genetics), University of Washington Medical Center, Seattle, Washington 98195; Department of Neurology (Division of Neurogenetics), University of Washington Medical Center, Seattle, Washington 98195
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