Development of the amphibian vestibular organ is regulated by molecular and neuronal mechanisms and by environmental input. The molecular component includes inductive signals derived from neural tissue of the hindbrain and from the surrounding mesoderm. The integrity of hindbrain patterning, on the other hand, depends on instructive signals from the isthmus organizer of the midbrain including the transcription factor XTcf-4. If the development of the vestibular system depends on the integrity of the isthmus as organizing centre, suppression of isthmus maintenance should modify vestibular morphology and function. We tested this hypothesis by down-regulation of the transcription factor XTcf-4. 10 pMol XTcf-4-specific antisense morpholino oligonucleotide were injected in one blastomere of 2-cell stage embryos of Xenopus laevis. For reconstitution experiments, 500 pg mRNA of the repressing XTcf-4A isoform or the activating XTcf-4C isoform were co-injected. Over-expression experiments were included using the same isoforms. Otoconia formation and vestibular controlled behaviour such as the roll-induced vestibuloocular reflex (rVOR) and swimming were recorded two weeks later. In 50% of tadpoles, down-regulation of XTcf-4 induced (1) a depression of otoconia formation accompanied by a reduction of the rVOR, (2) abnormal tail development, and (3) loop swimming behaviour. (4) All effects were rescued by co-injection of XTcf-4C but not or only partially by XTcf-4A. (5) Over-expression of XTcf-4A caused similar morphological and rVOR modifications as XTcf-4 depletion while over-expression of XTcf-4C had no effect. Because XTcf-4C has been described as essential factor for isthmus development, we postulate that the isthmus is strongly involved in vestibular development.

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