BMP heterodimers signal via distinct type I receptor class functions

Proc Natl Acad Sci U S A. 2021 Apr 13;118(15):e2017952118. doi: 10.1073/pnas.2017952118.


Heterodimeric TGF-β ligands outperform homodimers in a variety of developmental, cell culture, and therapeutic contexts; however, the mechanisms underlying this increased potency remain uncharacterized. Here, we use dorsal-ventral axial patterning of the zebrafish embryo to interrogate the BMP2/7 heterodimer signaling mechanism. We demonstrate that differential interactions with BMP antagonists do not account for the reduced signaling ability of homodimers. Instead, we find that while overexpressed BMP2 homodimers can signal, they require two nonredundant type I receptors, one from the Acvr1 subfamily and one from the Bmpr1 subfamily. This implies that all BMP signaling within the zebrafish gastrula, even BMP2 homodimer signaling, requires Acvr1. This is particularly surprising as BMP2 homodimers do not bind Acvr1 in vitro. Furthermore, we find that the roles of the two type I receptors are subfunctionalized within the heterodimer signaling complex, with the kinase activity of Acvr1 being essential, while that of Bmpr1 is not. These results suggest that the potency of the Bmp2/7 heterodimer arises from the ability to recruit both Acvr1 and Bmpr1 into the same signaling complex.

Keywords: BMP; bone morphogenetic protein; heterodimers; signaling; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / metabolism
  • Animals
  • Bone Morphogenetic Protein 2 / genetics
  • Bone Morphogenetic Protein 2 / metabolism*
  • Bone Morphogenetic Protein 7 / genetics
  • Bone Morphogenetic Protein 7 / metabolism*
  • Bone Morphogenetic Protein Receptors / genetics
  • Bone Morphogenetic Protein Receptors / metabolism*
  • Gastrula / metabolism
  • Mutation
  • Protein Binding
  • Protein Multimerization
  • Signal Transduction*
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*


  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 7
  • Zebrafish Proteins
  • bmp2b protein, zebrafish
  • bmp7a protein, zebrafish
  • bmpr1aa protein, zebrafish
  • bmpr1ab protein, zebrafish
  • Activin Receptors, Type I
  • Bone Morphogenetic Protein Receptors