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J. Biol. Chem., Vol. 282, Issue 52, 37894-37905, December 28, 2007

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Highly Conserved Sequences Mediate the Dynamic Interplay of Basic Helix-Loop-Helix Proteins Regulating Retinogenesis^*

Julio Hernandez, Lidia Matter-Sadzinski, Dorota Skowronska-Krawczyk¹, Florence Chiodini, Christine Alliod, Marc Ballivet, and Jean-Marc Matter²

From the Department of Biochemistry, Sciences II and Department of Ophthalmology, School of Medicine, University of Geneva, 1211 Genève 4, Switzerland

The atonal homolog 5 (ATH5) protein is central to the transcriptional network regulating the specification of retinal ganglion cells, and its expression comes under the spatiotemporal control of several basic helix-loop-helix (bHLH) proteins in the course of retina development. Monitoring the in vivo occupancy of the ATH5 promoter by the ATH5, Ngn2, and NeuroM proteins and analyzing the DNA motifs they bind, we show that three evolutionarily conserved E-boxes are required for the bHLH proteins to control the different phases of ATH5 expression. E-box 4 mediates the activity of Ngn2, ATH5, and NeuroM along the pathway leading to the conversion of progenitors into newborn neurons. E-box 1, by mediating the antagonistic effects of Ngn2 and HES1 in proliferating progenitors, controls the expansion of the ATH5 expression domain in early retina. E-box 2 is required for the positive feedback by ATH5 that underlies the up-regulation of ATH5 expression when progenitors are going through their last cell cycle. The combinatorial nature of the regulation of the ATH5 promoter suggests that the bHLH proteins involved have no assigned E-boxes but use a common set at which they either cooperate or compete to finely tune ATH5 expression as development proceeds.

Received for publication, May 1, 2007 , and in revised form, September 28, 2007.

^* This work was supported by the Swiss National Science Foundation, the ProVisu Foundation, and the State of Geneva. 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 Present address: University of California, San Diego, CMM-West 9500, Gilman Dr., MC 0648 La Jolla, CA 92093-0648.

² To whom correspondence should be addressed: Sciences II, 30 quai Ernest-Ansermet, 1211 Genève 4, Switzerland. E-mail: Jean-Marc.Matter{at}biochem.unige.ch.

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