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Retinoic acid rescues inner ear defects in Hoxa1 deficient mice

Nature Genetics volume 29, pages 34–39 (2001)Cite this article

Abstract

Little is known about the genetic pathways involved in the early steps of inner ear morphogenesis. Hoxa1 is transiently expressed in the developing hindbrain; its targeted inactivation in mice results in severe abnormalities of the otic capsule and membranous labyrinth 1. Here we show that a single maternal administration of a low dose of the vitamin A metabolite retinoic acid is sufficient to compensate the requirement for Hoxa1 function. It rescues cochlear and vestibular defects in mutant fetuses without affecting the development of the wildtype fetuses. These results identify a temporal window of susceptibility to retinoids that is critical for mammalian inner ear specification, and provide the first evidence that a subteratogenic dose of vitamin A derivative can be effective in rescuing a congenital defect in the mammalian embryo.

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Figure 1: Rescue of auditory capsule skeletal morphology.
Figure 2: Rescue of epithelial inner ear morphogenesis.
Figure 3: Rescue of inner ear histological organization.
Figure 4: Molecular rescue of inner ear structures.
Figure 5: Transient Hoxb1 response to 5RA treatment.
Figure 6: Molecular rescue in the rhombomere (r)5-r6 region of 5RA-treated mutants.

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Acknowledgements

We thank P. Chambon, M. Mallo, M. Leid, O. Abdel-Samad and the referees for insightful comments on an earlier version of this manuscript. We are grateful to M. Poulet and T. Ding for excellent technical assistance. We wish to thank J-L. Vonesch and D. Hentsch for valuable help with imaging. We acknowledge the following colleagues for kind gifts of reagents: P. Chambon, R. Krumlauf, P. Gruss, D. Henrique, C. Petit and D.Wilkinson. M.P. was supported by fellowships from the European Commission (EEC), EMBO, and Association pour la Recherche sur le Cancer. R.N. was supported by DAAD and Fondation pour la Recherche Médicale (FRM) fellowships. M.D. was supported by fellowships from the Ligue Nationale Contre le Cancer and FRM. This work was supported by grants to F.M.R. from the EEC Quality of Life Program, the Association pour la Recherche sur le Cancer, the Ministère pour le Recherche and by institutional funds from CNRS, INSERM and Hôpital Universitaire de Strasbourg.

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  1. Marc Davenne

    Present address: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, 11724, New York, USA

  2. Rüdiger Neun

    Present address: Max-Planck-Institut für Infektionsbiologie, Abteilung Molekulare Biologie, Campus Charité-Mitte, Schumannstrasse 21/22, D-10117, Berlin, Germany

  3. Massimo Pasqualetti and Rüdiger Neun: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, C.U. de Strasbourg, Illkirch Cedex, BP 163-67404, France

    Massimo Pasqualetti, Rüdiger Neun, Marc Davenne & Filippo M. Rijli

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Pasqualetti, M., Neun, R., Davenne, M. et al. Retinoic acid rescues inner ear defects in Hoxa1 deficient mice. Nat Genet 29, 34–39 (2001). https://doi.org/10.1038/ng702

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