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Rere controls retinoic acid signalling and somite bilateral symmetry

Nature volume 463, pages 953–957 (2010)Cite this article

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Abstract

One of the most notable features of the vertebrate body plan organization is its bilateral symmetry, evident at the level of vertebrae and skeletal muscles. Here we show that a mutation in Rere (also known as atrophin2) leads to the formation of asymmetrical somites in mouse embryos, similar to embryos deprived of retinoic acid1,2,3,4. Furthermore, we also demonstrate that Rere controls retinoic acid signalling, which is required to maintain somite symmetry by interacting with Fgf8 in the left–right signalling pathway. Rere forms a complex with Nr2f2, p300 (also known as Ep300) and a retinoic acid receptor, which is recruited to the retinoic acid regulatory element of retinoic acid targets, such as the Rarb promoter. Furthermore, the knockdown of Nr2f2 and/or Rere decreases retinoic acid signalling, suggesting that this complex is required to promote transcriptional activation of retinoic acid targets. The asymmetrical expression of Nr2f2 in the presomitic mesoderm overlaps with the asymmetry of the retinoic acid signalling response, supporting its implication in the control of somitic symmetry. Misregulation of this mechanism could be involved in symmetry defects of the human spine, such as those observed in patients with scoliosis.

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Figure 1: Asymmetric somite formation in Rere (om ) mutant mouse embryos is downstream of the left–right machinery.
Figure 2: Functional interaction of Rere and the retinoic acid pathway.
Figure 3: Regulation of retinoic acid signalling by Rere, Nr2f2, Rar and p300.
Figure 4: Retinoic acid signalling and Nr2f2 expression are asymmetric across the left–right axis in the presomitic mesoderm of early-somite stage embryos.

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Acknowledgements

We thank members of the Pourquié laboratory for discussions and comments on the manuscript, H. Li for help with the statistics, J. Chatfield for editorial assistance and S. Esteban for artwork. We are grateful to D. Henrique for critical reading of the manuscript. We thank J. Rossant, G. Martin and P. Dollé for providing mouse lines. We thank the Stowers Institute Core Facilities, especially D. Dukes and B. Lewis in the Laboratory Animal Service Facility. G.C.V.-N. was funded by the Portuguese Fundação para a Ciência e Tecnologia (FCT). K.T.S. is funded by the American Cancer Society. M.V.-C. was supported by l’Association de Langue Française pour l’Etude du Diabète et des Maladies Métaboliques (grant from ALFEDIAM-GlaxoSmithKline) and Bonus Qualité Recherche, Université Paris Descartes. This research was supported by the Howard Hughes Medical Institute, the Stowers Institute for Medical Research and the Muscular Dystrophy Association.

Author Contributions G.C.V.-N. and O.P. designed the experiments. G.C.V.-N. performed and analysed the experiments with O.P. M.M., K.T.S. and G.C.V.-N. performed the ChIP experiments. A.S.P. and M.V.-C. provided genetically modified mice. G.C.V.-N., M.M., K.T.S., J.L.W. and O.P. wrote the manuscript. All authors discussed and agreed on the results and commented on the manuscript. O.P. supervised the project.

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  1. Gonçalo C. Vilhais-Neto, Mitsuji Maruhashi & Olivier Pourquié

    Present address: Present address: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS (UMR 7104), Inserm U964, Université de Strasbourg, Illkirch F-67400, France.,

Authors and Affiliations

  1. Stowers Institute for Medical Research,,

    Gonçalo C. Vilhais-Neto, Mitsuji Maruhashi, Karen T. Smith, Jerry L. Workman & Olivier Pourquié

  2. Howard Hughes Medical Institute, Kansas City, Missouri 64110, USA ,

    Mitsuji Maruhashi & Olivier Pourquié

  3. Department of Endocrinology, Metabolism, and Cancer, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Inserm U567, Paris, France,

    Mireille Vasseur-Cognet

  4. Genentech, South San Francisco, California 94080, USA ,

    Andrew S. Peterson

  5. University of Kansas Medical Center, Kansas City, Kansas 66160, USA ,

    Olivier Pourquié

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Vilhais-Neto, G., Maruhashi, M., Smith, K. et al. Rere controls retinoic acid signalling and somite bilateral symmetry. Nature 463, 953–957 (2010). https://doi.org/10.1038/nature08763

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