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Background   Otx  genes, orthologues of the  Drosophila orthodenticle  gene ( otd ), play crucial roles in vertebrate brain development. In the  Xenopus  eye,  Xotx2  and  Xotx5b  promote bipolar and photoreceptor cell fates, respectively. The molecular basis of their differential action is not completely understood, though the carboxyl termini of the two proteins seem to be crucial. To define the molecular domains that make the action of these proteins so different, and to determine whether their retinal abilities are shared by  Drosophila  OTD, we performed an  in vivo  molecular dissection of their activity by transfecting retinal progenitors with several wild-type, deletion and chimeric constructs of  Xotx2 ,  Xotx5b  and  otd .    Results  We identified a small 8–10 amino acid divergent region, directly downstream of the homeodomain, that is crucial for the respective activities of XOTX2 and XOTX5b. In lipofection experiments, the exchange of this 'specificity box' completely switches the retinal activity of XOTX5b into that of XOTX2 and  vice versa . Moreover, the insertion of this box into  Drosophila  OTD, which has no effect on retinal cell fate, endows it with the specific activity of either XOTX protein. Significantly, in cell transfection experiments, the diverse ability of XOTX2 and XOTX5b to synergize with NRL, a cofactor essential for vertebrate rod development, to transactivate the rhodopsin promoter is also switched depending on the box. We also show by GST-pull down that XOTX2 and XOTX5b differentially interact with NRL, though this property is not strictly dependent on the box.    Conclusion  Our data provide molecular evidence on how closely related homeodomain gene products can differentiate their functions to regulate distinct cell fates. A small 'specificity box' is both necessary and sufficient to confer on XOTX2 and XOTX5b their distinct activities in the developing frog retina and to convert the neutral orthologous OTD protein of  Drosophila  into a positive and specific XOTX-like retinal regulator. Relatively little is known of what gives developmental specificity to homeodomain regulators. We propose that this box is a major domain of XOTX proteins that provides them with the appropriate developmental specificity in retinal histogenesis.

A specific box switches the cell fate determining activity of XOTX2 and XOTX5b in the Xenopus retina