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Scaling of the BMP activation gradient in Xenopus embryos

Abstract

In groundbreaking experiments, Hans Spemann demonstrated that the dorsal part of the amphibian embryo can generate a well-proportioned tadpole, and that a small group of dorsal cells, the ‘organizer’, can induce a complete and well-proportioned twinned axis when transplanted into a host embryo. Key to organizer function is the localized secretion of inhibitors of bone morphogenetic protein (BMP), which defines a graded BMP activation profile. Although the central proteins involved in shaping this gradient are well characterized, their integrated function, and in particular how pattern scales with size, is not understood. Here we present evidence that in Xenopus, the BMP activity gradient is defined by a ‘shuttling-based’ mechanism, whereby the BMP ligands are translocated ventrally through their association with the BMP inhibitor Chordin. This shuttling, with feedback repression of the BMP ligand Admp, offers a quantitative explanation to Spemann’s observations, and accounts naturally for the scaling of embryo pattern with its size.

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Figure 1: Numerical evidence for shuttling.
Figure 2: Shuttling model supports size compensation and secondary-axis induction.
Figure 3: Direct visualization of BMP4 shuttling by Chordin.
Figure 4: Experimental evidence for shuttling in Xenopus.

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Acknowledgements

We thank J. Christian for the BMP4 constructs, and the members of our groups for discussions and help with the experiments. This work was supported by Minerva, the Israel Science Foundation and the Hellen and Martin Kimmel award for innovative investigations to N.B. and a grant from the Israel Science Foundation and the Wolfson Family Chair in Genetics to A.F. B-Z.S. holds the Hilda and Cecil Lewis Professorial chair in Molecular Genetics.

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Correspondence to Abraham Fainsod or Naama Barkai.

Supplementary information

Supplementary Information

The Supplementary Information section contains the following: 1. Figure describing the Xenopus and Drosophila dorsoventral patterning network, and a schematic representation of the inhibition and shuttling mechanisms. 2. Details of the numerical screen. 3. Detailed list of parameters used to generate the figures in the main text. 4. Analytical treatment of the steady state of the shuttling model. 5. Analytical treatment of the general model. 6. Analysis of the effect of the mutual regulation of BMP ligands and Chordin. 7. Formalization of the system using dimensionless equations. 8. Numerical solution of an extended model for the dorsoventral patterning, including the BMP receptors and Tsg. 9. Discussion of the geometry of the model. (PDF 657 kb)

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Ben-Zvi, D., Shilo, BZ., Fainsod, A. et al. Scaling of the BMP activation gradient in Xenopus embryos. Nature 453, 1205–1211 (2008). https://doi.org/10.1038/nature07059

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