Forebrain and midbrain development requires epiblast-restricted Otx2 translational control mediated by its 3 ' UTR

Otx genes play an important role in brain development. Previous mouse model s suggested that the untranslated regions (UTRs) of Otx2 mRNA may contain r egulatory element(s) required for its post-transcriptional control in epibl ast and neuroectoderm. In order to study this, we have perturbed the 3' UTR of Otx2 by inserting a small fragment of DNA from the lambda phage. Otx2(l ambda) mutants exhibited proper gastrulation and normal patterning of the e arly anterior neural plate, but from 8.5 days post coitum they developed se vere forebrain and midbrain abnormalities. OTX2 protein levels in Otx2(lamb da) mutants were heavily reduced in the epiblast, axial mesendoderm and ant erior neuroectoderm but not in the visceral endoderm. At the molecular leve l, we found out that the ability of the Otx2(lambda) mRNA to form efficient polyribosome complexes was impaired. Sequence analysis of the Otx2-3' UTR revealed a 140 bp long element that is present only in vertebrate Otx2 gene s and conserved in identity by over 80 %. Our data provide experimental evi dence that murine brain development requires accurate translational control of Otx2 mRNA in epiblast and neuronal progenitor cells. This leads us to h ypothesise that this control might have important evolutionary implications .