Retinoic acid signalling links left–right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo

Abstract

During embryogenesis, cells are spatially patterned as a result of highly coordinated and stereotyped morphogenetic events. In the vertebrate embryo, information on laterality is conveyed to the node, and subsequently to the lateral plate mesoderm, by a complex cascade of epigenetic and genetic events, eventually leading to a left–right asymmetric body plan. At the same time, the paraxial mesoderm is patterned along the anterior–posterior axis in metameric units, or somites, in a bilaterally symmetric fashion. Here we characterize a cascade of laterality information in the zebrafish embryo and show that blocking the early steps of this cascade (before it reaches the lateral plate mesoderm) results in random left–right asymmetric somitogenesis. We also uncover a mechanism mediated by retinoic acid signalling that is crucial in buffering the influence of the flow of laterality information on the left–right progression of somite formation, and thus in ensuring bilaterally symmetric somitogenesis.

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Figure 1: Cascade of LR asymmetric information in the zebrafish.
Figure 2: LR asymmetric somitogenesis in zebrafish embryos.
Figure 3: RA signalling coordinates LR somitogenesis in zebrafish embryos.
Figure 4: Desynchronization of the molecular clock in raldh2 morphants.
Figure 5: RA signalling counteracts the LR information flow during zebrafish somitogenesis.
Figure 6: Crosstalk between LR and AP axes.

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Acknowledgements

We thank T. Tsukui, H. Takeda and A. Smolka for sharing reagents; N. Hirokawa and P. Dollé for sharing results before publication; C. Kintner for helpful suggestions; all members of the laboratory for discussions; I. Dubova for help with fish procedures; C. Callol, T. Chapman, H. Kawakami and M. Sugii for technical assistance; and M.-F. Schwarz for help in the preparation of this manuscript. A.R. and C.R.-E. are partly supported by postdoctoral fellowships from Fundación Inbiomed, Spain. This study was funded by the NIH, the Human Frontier Science Program, and the G. Harold and Leila Y. Mathers Charitable Foundation.

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Correspondence to Juan Carlos Izpisúa Belmonte.

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Supplementary information

Supplementary Figures

Contains three Supplementary Figures, S1-S3 and additional references. Supplementary Figure S1 details the H+/K+-ATPase α immunoreactivity in zebrafish embryos. Supplementary Figure S2 shows the alterations in somitogenesis after inhibition of FGF and/or Wnt signalling. Supplementary Figure S3 details the expression of RA receptors in the zebrafish embryo. (DOC 297 kb)

Supplementary Table S1

Left-right bias of asymmetric somitogenesis. (DOC 51 kb)

Supplementary Methods

This contains additional details of the methods used in our study. (DOC 22 kb)

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Kawakami, Y., Raya, Á., Raya, R. et al. Retinoic acid signalling links left–right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo. Nature 435, 165–171 (2005). https://doi.org/10.1038/nature03512

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