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J. Biol. Chem., Vol. 278, Issue 24, 21721-21731, June 13, 2003

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OTX2 Activates the Molecular Network Underlying Retina Pigment Epithelium Differentiation^*

Juan Ramón Martínez-Morales  , Vincent Dolez ¶, Isabel Rodrigo , Raffaella Zaccarini ¶, Laurence Leconte ¶, Paola Bovolenta  || ** and Simon Saule ¶ || 

From the Instituto Cajal, Consejo Superior de Investigaciones Científicas, Dr. Arce 37, Madrid 28002, Spain, ^¶ Unitée Mixte de Reserche 146, Institut Curie Section de Recherche, Batiment 110, Centre Universitaire, Orsay 91405 cedex, France

The retina pigment epithelium (RPE) is fundamental for the development and function of the vertebrate eye. Molecularly, the presumptive RPE can be identified by the early expression of two transcription factors, Mitf and Otx. In mice deficient for either gene, RPE development is impaired with loss of melanogenic gene expression, raising the possibility that in the eye OTX proteins operate either in a feedback loop or in cooperation with MITF for the control of RPE-specific gene expression. Here we show that Otx2 induces a pigmented phenotype when overexpressed in avian neural retina cells. In addition, OTX2 binds specifically to a bicoid motif present in the promoter regions of three Mitf target genes, QNR71, TRP-1, and tyrosinase, leading to their transactivation. OTX2 and MITF co-localize in the nuclei of RPE cells and physically interact, and their co-expression results in a cooperative activation of QNR71 and tyrosinase promoters. Collectively, these data suggest that both transcription factors operate at the same hierarchical level to establish the identity of the RPE.

Received for publication, February 19, 2003 , and in revised form, March 26, 2003.

Note Added in Proof—A recent paper by the group of Shigeki Shibahara shows that OTX2 binds and activates also the DOPAchrome tautomerase gene (TRP2) promoter, adding further evidence to the idea that Otx2 is required for the differentiation of the RPE (Takeda, K., Yokoyama, S., Yasumoto, K., Saito, H., Udono, T., Takahashi, K., and Shibahara, S. (2003) Biochem. Biophys. Res. Commun. 300, 908–914).

^* This study was supported in part by grants from the Spanish Ministerio Ciencia y Tecnología (Grant BMC-2001-0818), the European Union (Grant QLRT-2000-01460), and Human Frontier Science Program Organisation (RGP0040/2001-M) (to P. B.) and by the Association pour la Recherché sur le Cancer and the Association Retina France (to S. S.). 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.

Postdoctoral work was supported by the Comunidad Autónoma de Madrid.

^|| Co-senior authors.

^** To whom correspondence may be addressed. Tel.: 34-91-585-4717; Fax: 34-91-585-4754; E-mail: bovolenta{at}cajal.csic.es. To whom correspondence may be addressed. Tel.: 33-1-69-86-7153; Fax: 33-1-69-07-4525; E-mail: Simon.Saule{at}curie.u-psud.fr.

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