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J. Biol. Chem., Vol. 281, Issue 37, 27327-27334, September 15, 2006

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Retinoic Acid Regulates the Expression of Photoreceptor Transcription Factor NRL^*

Hemant Khanna, Masayuki Akimoto, Sandrine Siffroi-Fernandez^¶, James S. Friedman¹, David Hicks^¶, and Anand Swaroop, Harold F. Falls Collegiate Professor and a recipient of RPB Senior Scientific Investigator award^||2

From the Departments of Ophthalmology and Visual Sciences and ^||Human Genetics, University of Michigan, Ann Arbor, Michigan 48105, the Translational Research Center, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan, the ^¶Laboratory of Neurobiological Rhythms, UMR CNRS 7518, Centre de Neurochimie, 67084 Strasbourg, France

NRL (neural retina leucine zipper) is a key basic motif-leucine zipper (bZIP) transcription factor, which orchestrates rod photoreceptor differentiation by activating the expression of rod-specific genes. The deletion of Nrl in mice results in functional cones that are derived from rod precursors. However, signaling pathways modulating the expression or activity of NRL have not been elucidated. Here, we show that retinoic acid (RA), a diffusible factor implicated in rod development, activates the expression of NRL in serum-deprived Y79 human retinoblastoma cells and in primary cultures of rat and porcine photoreceptors. The effect of RA is mimicked by TTNPB, a RA receptor agonist, and requires new protein synthesis. DNaseI footprinting and electrophoretic mobility shift assays (EMSA) using bovine retinal nuclear extract demonstrate that RA response elements (RAREs) identified within the Nrl promoter bind to RA receptors. Furthermore, in transiently transfected Y79 and HEK293 cells the activity of Nrl-promoter driving a luciferase reporter gene is induced by RA, and this activation is mediated by RAREs. Our data suggest that signaling by RA via RA receptors regulates the expression of NRL, providing a framework for delineating early steps in photoreceptor cell fate determination.

Received for publication, June 8, 2006 , and in revised form, July 3, 2006.

^* This research was supported in part by Grants EY011115, EY007003 from the National Institutes of Health, The Foundation Fighting Blindness (FFB), and Research to Prevent Blindness (RPB). 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 FFB-Canada postdoctoral fellowship.

² To whom correspondence should be addressed: Dept. of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, 1000 Wall St., Ann Arbor, MI 48105. Tel.: 734-763-3731; Fax: 734-647-0228; E-mail: swaroop{at}umich.edu.

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