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Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis

Nature Cell Biology volume 11, pages 637–643 (2009)Cite this article

Abstract

Patterning the embryonic dorsoventral axis of both vertebrates and invertebrates requires signalling through bone morphogenetic proteins (BMPs)1. Although a well-studied process, the identity of the physiologically relevant BMP signalling complex in the Drosophila melanogaster embryo is controversial2,3, is generally inferred from cell culture studies and has not been investigated in vertebrates. Here, we demonstrate that dorsoventral patterning in zebrafish, Danio rerio, requires two classes of non-redundant type I BMP receptors, Alk3/6 and Alk8 (activin-like kinases 3/6 and 8). We show, under physiological conditions in the embryo, that these two type I receptor classes form a complex in a manner that depends on Bmp2 and Bmp7. We found that both Bmp2–7 heterodimers, as well as Bmp2 and Bmp7 homodimers, form in the embryo. However, only recombinant ligand heterodimers can activate BMP signalling in the early embryo, whereas a combination of Bmp2 and Bmp7 homodimers cannot. We propose that only heterodimers, signalling through two distinct classes of type I receptor, possess sufficient receptor affinity in an environment of extracellular antagonists to elicit the signalling response required for dorsoventral patterning.

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Figure 1: Knockdown of alk3a/b with alk6a/b causes increasingly severe dorsalization and loss of P-Smad1/5.
Figure 2: Alk3/6 and Alk8 function non-redundantly and independently.
Figure 3: Homodimers and heterodimers are present in the zebrafish embryo.
Figure 4: Bmp2–Bmp7 heterodimers pattern the zebrafish embryo.
Figure 5: Alk3a and Alk8 associate in a complex only when Bmp2b and Bmp7 are present.

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Acknowledgements

We thank M. Whitman for the Alk4(KR)HA construct; L. Jing and M. Granato for Myc-tagged Unplugged/MuSK; B. Holloway and J. Tucker for technical advice; S. Lu for technical support; J. Xie and the UPenn zebrafish core facility for wild-type embryos and S. DiNardo, T. Gupta, F. Marlow and L. Kapp for comments on the manuscript. This work was funded by NIH grants to M.C.M. (GM56326) and to S.C.L. (5 T32 GM07229-28 and 2 T32 HD007516-05).

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  1. Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, 1211 BRBII/III, 421 Curie Boulevard., Philadelphia, 19104-6058, PA, USA

    Shawn C. Little & Mary C. Mullins

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S.C.L. performed the experiments. S.C.L. and M.C.M. designed the experiments, analysed the data, and wrote the manuscript.

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Correspondence to Mary C. Mullins.

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Little, S., Mullins, M. Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis. Nat Cell Biol 11, 637–643 (2009). https://doi.org/10.1038/ncb1870

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