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J. Biol. Chem., Vol. 281, Issue 2, 744-751, January 13, 2006

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CHX10 Targets a Subset of Photoreceptor Genes^*

Kimberley M. Dorval¶1, Brian P. Bobechko¶, Hiroki Fujieda, Shiming Chen||**, Don J. Zack2, and Rod Bremner¶3

From the Toronto Western Research Institute, University Health Network, Departments of Laboratory Medicine and Pathobiology and Ophthalmology and Visual Sciences, ^¶Vision Science Research Program, University of Toronto, Toronto, Ontario M5T 2S8, Canada, the Departments of ^||Ophthalmology and Visual Sciences, ^**Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, and the Departments of Ophthalmology, Molecular Biology and Genetics, and Neuroscience, and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277

The homeobox gene CHX10 is required for retinal progenitor cell proliferation early in retinogenesis and subsequently for bipolar neuron differentiation. To clarify the molecular mechanisms employed by CHX10 we sought to identify its target genes. In a yeast one-hybrid assay Chx10 interacted with the Ret1 site of the photoreceptor-specific gene Rhodopsin. Gel shift assays using in vitro translated protein confirmed that CHX10 binds to Ret1, but not to the similar Rhodopsin sites Ret4 and BAT-1. Using retinal nuclear lysates, we observed interactions between Chx10 and additional photoreceptor-specific elements including the PCE-1 (Rod arrestin/S-antigen) and the Cone opsin locus control region (Red/green cone opsin). However, chromatin immunoprecipitation assays revealed that in vivo, Chx10 bound sites upstream of the Rod arrestin and Interphotoreceptor retinoid-binding protein genes but not Rhodopsin or Cone opsin. Thus, in a chromatin context, Chx10 associates with a specific subset of elements that it binds with comparable apparent affinity in vitro. Our data suggest that CHX10 may target these motifs to inhibit rod photoreceptor gene expression in bipolar cells.

Received for publication, August 26, 2005 , and in revised form, October 13, 2005.

^* This work was supported in part by the Canadian Institutes for Health Research and National Institutes of Health R01EY009769, and generous gifts from The Guerrieri Family Foundation and Robert and Clarice Smith. 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.

¹ Recipient of a Vision Science Research Program Doctoral Research Award from the University of Toronto and an E. A. Baker Foundation and The Canadian National Institute for the Blind/CIHR Partnership Doctoral Research Fellowship.

² Guerrieri Professor of Genetic Engineering and Molecular Ophthalmology and the recipient of a Research to Prevent Blindness Senior Investigator Award.

³ To whom correspondence should be addressed: MC6–424, Cellular and Molecular Division, 399 Bathurst St., Toronto, Ontario M5T 2S8, Canada. Tel.: 416-603-5865; Fax: 416-603-5126; E-mail: rbremner{at}uhnres.utoronto.ca.

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