May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Atrophins Are Corepressors for NR2E3
Author Affiliations & Notes
  • P. Escher
    Institute of Research in Ophthalmology, Sion, University of Lausanne, EPFL-Ecole Polytechnique Fédérale, Lausanne, Switzerland
  • R. Roduit
    Institute of Research in Ophthalmology, Sion, University of Lausanne, EPFL-Ecole Polytechnique Fédérale, Lausanne, Switzerland
  • T. Favez
    Institute of Research in Ophthalmology, Sion, University of Lausanne, EPFL-Ecole Polytechnique Fédérale, Lausanne, Switzerland
  • N. Voirol
    Institute of Research in Ophthalmology, Sion, University of Lausanne, EPFL-Ecole Polytechnique Fédérale, Lausanne, Switzerland
  • S. Chen
    Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, Missouri
  • C.-C. Tsai
    Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey
  • D. F. Schorderet
    Institute of Research in Ophthalmology, Sion, University of Lausanne, EPFL-Ecole Polytechnique Fédérale, Lausanne, Switzerland
  • Footnotes
    Commercial Relationships P. Escher, None; R. Roduit, None; T. Favez, None; N. Voirol, None; S. Chen, None; C. Tsai, None; D.F. Schorderet, None.
  • Footnotes
    Support NIH Grant EY12543, Research to Prevent Blindness
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 2925. doi:
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      P. Escher, R. Roduit, T. Favez, N. Voirol, S. Chen, C.-C. Tsai, D. F. Schorderet; Atrophins Are Corepressors for NR2E3. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2925.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: Photoreceptor cell fate is determined by a complex transcriptional regulatory system. Whereas many transcription factors are involved in retinal progenitor cell proliferation, the cone-rod homeobox protein CRX appears to be a master regulator of the commitment of retinal progenitors towards the photoreceptor lineage. A current model proposes that in rods CRX interacts with NRL (neural retina-specific leucine zipper protein) to specify a rod-specific gene expression. The photoreceptor-selective nuclear hormone receptor NR2E3 is hypothesized to repress the CRX/NRL-mediated transcription of cone-specific genes by interacting with corepressors. Importance of this repression is exemplified by the association of mutations in nr2e3 with enhanced S-cone syndrome (ESCS). We aim at identifying candidate corepressors for NR2E3-mediated transrepression.

Methods:: By cell culture-based transactivation assays in 293T cells, we test the corepressor activity of atrophin-1, atrophin-2 and NCoR on rhodopsin and M-opsin promoters, cotransfecting CRX and NRL, together with NR2E3 wild-type and mutant proteins. Molecular interactions are further tested by co-immunoprecipitation, chromatin-immunoprecipitation, gel-retardation assays, BRET and in situ hybridization.

Results:: Both atrophin-1 and atrophin-2 proteins mediate repression of the M-opsin promoter in the presence of NR2E3. Transactivation mediated by CRX alone is also repressed by atrophins, whereas that of NRL is not. Interestingly, NR2E3R311Q, the most common mutation found in ESCS patients, shows impaired repression when coexpressed with atrophins in our transactivation assays.

Conclusions:: In addition to the reported interaction of atrophins with NR2E1, we show that this class of corepressors is also interacting with NR2E3. The differential repression mediated by atrophins with wild-type and mutant NR2E3 strongly suggests a physiological relevance of NR2E3/atrophin interactions in photoreceptors in vivo.

Keywords: transcription factors • transcription • retinal development 
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