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Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development

Nature Genetics volume 31, pages 84–88 (2002)Cite this article

Abstract

Retinoic acid, the active derivative of vitamin A (retinol), is a hormonal signaling molecule that acts in developing and adult tissues1. The Cyp26a1 (cytochrome p450, 26) protein metabolizes retinoic acid into more polar hydroxylated and oxidized derivatives2,3. Whether some of these derivatives are biologically active metabolites has been debated4,5. Cyp26a1−/− mouse fetuses have lethal morphogenetic phenotypes mimicking those generated by excess retinoic acid administration, indicating that human CYP26A1 may be essential in controlling retinoic acid levels during development6,7. This hypothesis suggests that the Cyp26a1−/− phenotype could be rescued under conditions in which embryonic retinoic acid levels are decreased. We show that Cyp26a1−/− mice are phenotypically rescued by heterozygous disruption of Aldh1a2 (also known as Raldh2), which encodes a retinaldehyde dehydrogenase responsible for the synthesis of retinoic acid during early embryonic development8,9. Aldh1a2 haploinsufficiency prevents the appearance of spina bifida and rescues the development of posterior structures (sacral/caudal vertebrae, hindgut, urogenital tract), while partly preventing cervical vertebral transformations and hindbrain pattern alterations in Cyp26a1−/− mice. Thus, some of these double-mutant mice can reach adulthood. This study is the first report of a mutation acting as a dominant suppressor of a lethal morphogenetic mutation in mammals. We provide genetic evidence that ALDH1A2 and CYP26A1 activities concurrently establish local embryonic retinoic acid levels that must be finely tuned to allow posterior organ development and to prevent spina bifida.

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Figure 1: Rescue of spina bifida and tail development in Cyp26−/−Aldh1a2+/− compound mutants.
Figure 2: Caudal vertebral development in Cyp26a1−/− and Cyp26a1−/−/Aldh1a2+/− mutants.
Figure 3: Tail and posterior organ development in Cyp26a1−/−/Aldh1a2+/− compound mutants.
Figure 4: Variable rescue of cervical vertebral transformations in Cyp26a1−/−Aldh1a2+/− double-mutants.
Figure 5: Partial rescue of abnormal anterior rhombomere patterning in Cyp26a1−/−Aldh1a2+/− double-mutants.
Figure 6: Retinoic acid–reporter transgene activity in embryos with single or compound mutations of Cyp26a1 and Aldh1a2.

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Acknowledgements

We thank J.M. Bornert and V. Fraulob for technical assistance. We are grateful to J. Rossant for providing the RARE-hsp-lacZ transgene. This work was supported by funds from the Centre National de la Recherche Scientifique, INSERM, the Collège de France, the Hôpitaux Universitaires de Strasbourg, the Association pour la Recherche sur le Cancer, the Fondation pour la Recherche Médicale and Bristol-Myers Squibb. S.A.A. holds a studentship from the Canadian Institutes of Health Research (CIHR), and M.P. is supported by the CIHR and the National Cancer Institute of Canada.

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Author notes

  1. Karen Niederreither

    Present address: Departments of Medicine and Molecular and Cellular Biology, Center for Cardiovascular Development, Baylor College of Medicine, Houston, Texas, USA

  2. Martin Petkovich, Pierre Chambon and Pascal Dollé: 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, BP 163, Illkirch Cedex, 67404, CU de Strasbourg, France

    Karen Niederreither, Brigitte Schuhbaur, Pierre Chambon & Pascal Dollé

  2. Department of Pathology, Cancer Research Laboratories, Queen's University, Kingston, Ontario, Canada

    Suzan Abu-Abed & Martin Petkovich

  3. Department of Biochemistry, Cancer Research Laboratories, Queen's University, Kingston, Ontario, Canada

    Martin Petkovich

Authors
  1. Karen Niederreither
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  2. Suzan Abu-Abed
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  3. Brigitte Schuhbaur
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  4. Martin Petkovich
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  5. Pierre Chambon
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  6. Pascal Dollé
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Correspondence to Pascal Dollé.

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Niederreither, K., Abu-Abed, S., Schuhbaur, B. et al. Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nat Genet 31, 84–88 (2002). https://doi.org/10.1038/ng876

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