The vertebrate otocyst, which gives rise to the structures of the inner ear, invaginates from the hindbrain surface epithelium adjacent to rhombomeres 5 and 6 (r5 and r6). Induction of the otocyst requires signals from the hindbrain neuroepithelium, so it is not surprising to find that mutations that affect the patterning of the r4–r6 region can cause profound defects in inner ear development. Hoxa1 is activated in r4–r6 around the time that the otocyst begins to develop, and its targeted disruption in the mouse leads to malformation of the vestibular apparatus and the cochlea. However, as reported in Nature Genetics, Pasqualetti et al. have now shown that these defects can be rescued by a sub-teratogenic dose of the vitamin A derivative retinoic acid (RA).

Although excess RA can severely disrupt hindbrain development, Pasqualetti et al. showed that a dose of 5 mg kg−1 was not teratogenic to wild-type embryos when administered from 8.0 days post coitum (dpc) onwards. Using this dose, they showed that vestibular and cochlear structures could be partially or fully rescued in Hoxa1−/− embryos if RA was administered between 8.0 and 8.75 dpc. Treatment outside this time period did not rescue the inner ear phenotype, indicating that there is a limited time window during which the RA response can compensate for the loss of Hoxa1 function.

The authors then analysed changes in gene expression in response to RA treatment. Hoxb1 , kreisler and Fgf3 are usually expressed within the r4–r6 region, but they are all downregulated in Hoxa1−/− embryos. In embryos treated with RA at 8.0 dpc + 2 h, the expression of all three genes was transiently restored. However, in embryos exposed to RA at 8.75 dpc, only Fgf3 was upregulated, yet inner ear development could still be rescued. This implies that Fgf3 expression might be sufficient to rescue inner ear structures in Hoxa1−/− embryos, and that RA can replace the function of Hoxa1 in activating the Fgf3 signalling pathway.

So, this study points to a molecular mechanism through which Hoxa1 might exert its effect on inner ear development, but Pasqualetti et al. argue that it could also have wider implications. The use of vitamin supplements during pregnancy is controversial, and its benefits are unclear, but there is no evidence that the amount of vitamin A in commercially available vitamin preparations is harmful to the fetus, and the authors suggest that there might be certain circumstances when it could even be beneficial.