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J. Biol. Chem., Vol. 279, Issue 45, 47272-47277, November 5, 2004

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Pax6 Interacts with cVax and Tbx5 to Establish the Dorsoventral Boundary of the Developing Eye^*

Laurence Leconte, Laure Lecoin, Patrick Martin, and Simon Saule¶

From the CNRS UMR 146, Institut Curie Section de Recherche, Btiment 110, Centre Universitaire, 91405 Orsay Cedex, France and CNRS UMR6548, Transcriptional Regulation and Differentiation, Btiment Sciences Naturelles, Parc Valrose, Universite de Nice, 06108 Nice cedex, France

Dorsoventral pattern formation of the optic cup is essential for vertebrate eye morphogenesis and retinotectal topographic mapping. Dorsal and ventral aspects of the eye are distinct at early stages of development; cVax homeodomain protein expression is confined to the ventral optic cup, whereas Tbx5 (T-box transcription factor) expression domain becomes restricted to the dorsal region. Misexpression of cVax or Tbx5 induces profound defects in eye morphology and abnormal visual projections. In the Pax6-/- mutant Tbx5 fails to be expressed, and Vax1 and -2 are abnormally present in the entire optic vesicle. During eye development Pax6 becomes expressed in a gradient at the optic cup stage due to the specific activation of a highly conserved intronic enhancer in the Pax6 locus. We observed that the highest level of Pax6 in the optic cup corresponds to the boundary between non-overlapping cVax and Tbx5 territories. To further investigate how these transcription factors control the patterning of the eye, we overexpressed Pax6 in the chick optic cup (E2) using in ovo electroporation. We observed that overexpression of Pax6 extends the Tbx5 and Bmp4 domains but reduces the cVax expression domains in the E3 chick eye. This results in an abnormal eye phenotype at E4. In addition, we showed that cVax and Tbx5 interact with Pax6 and modulate in an opposite manner the activity of the Pax6 enhancer. Moreover, the Pax6/cVax interaction inhibits the transactivation properties of Pax6. These results demonstrate that Pax6 together with cVax and Tbx5 mediate dorsoventral patterning of the eye.

Received for publication, June 14, 2004 , and in revised form, August 13, 2004.

^* This work was supported by the Curie Institute, CNRS, Association pour la Recherche Centre le Cancer, and Retina France. 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.

^¶ To whom correspondence should be addressed. Tel.: 33-1-6986-7153; Fax: 33-1-6907-4525; E-mail: Simon.Saule{at}curie.u-psud.fr.

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