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OTD/OTX2 functional equivalence depends on 5' and 3' UTR-mediated control of Otx2 mRNA for nucleo-cytoplasmic export and epiblast-restricted translation

Dario Acampora^1,2,, Pietro Pilo Boyl^1,, Massimo Signore¹, Juan Pedro Martinez-Barbera¹, Cristina Ilengo³, Eduardo Puelles¹, Alessandro Annino², Heinrich Reichert⁴, Giorgio Corte^3,5 and Antonio Simeone^1,2,*

¹ MRC Centre for Developmental Neurobiology, King’s College London, Guy’s Campus, New Hunts House, London SE1 9RT, UK
² International Institute of Genetics and Biophysics, CNR, Via G. Marconi 12, 80125 Naples, Italy
³ IST-National Institute for Cancer Research,
⁵ Dipartimento di Oncologia Clinica e Sperimentale, Università di Genova, Largo Benzi, 16132 Genova, Italy
⁴ Institute of Zoology, University of Basel, Rheinsprung 9, CH-4051 Basel, Switzerland
These authors contributed equally to the work

*Author for correspondence (e-mail: antonio.simeone{at}kcl.ac.uk)

Accepted September 12, 2001

How gene activity is translated into phenotype and how it can modify morphogenetic pathways is of central importance when studying the evolution of regulatory control mechanisms. Previous studies in mouse have suggested that, despite the homeodomain-restricted homology, Drosophila orthodenticle (otd) and murine Otx1 genes share functional equivalence and that translation of Otx2 mRNA in epiblast and neuroectoderm might require a cell type-specific post-transcriptional control depending on its 5' and 3' untranslated sequences (UTRs).

In order to study whether OTD is functionally equivalent to OTX2 and whether synthesis of OTD in epiblast is molecularly dependent on the post-transcriptional control of Otx2 mRNA, we generated a first mouse model (otd²) in which an Otx2 region including 213 bp of the 5' UTR, exons, introns and the 3' UTR was replaced by an otd cDNA and a second mutant (otd^2FL) replacing only exons and introns of Otx2 with the otd coding sequence fused to intact 5' and 3' UTRs of Otx2.

otd² and otd^2FL mRNAs were properly transcribed under the Otx2 transcriptional control, but mRNA translation in epiblast and neuroectoderm occurred only in otd^2FL mutants. Phenotypic analysis revealed that visceral endoderm (VE)-restricted translation of otd² mRNA was sufficient to rescue Otx2 requirement for early anterior patterning and proper gastrulation but it failed to maintain forebrain and midbrain identity.

Importantly, epiblast and neuroectoderm translation of otd^2FL mRNA rescued maintenance of anterior patterning as it did in a third mouse model replacing, as in otd^2FL, exons and introns of Otx2 with an Otx2 cDNA (Otx2^2c). The molecular analysis has revealed that Otx2 5' and 3' UTR sequences, deleted in the otd² mRNA, are required for nucleo-cytoplasmic export and epiblast-restricted translation. Indeed, these molecular impairments were completely rescued in otd^2FL and Otx2^2c mutants. These data provide novel in vivo evidence supporting the concept that during evolution pre-existing gene functions have been recruited into new developmental pathways by modifying their regulatory control.

Key words: otd, Otx2, UTR, Translational control, VE, Anterior patterning, Brain evolution, Mouse

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