Integration of Nodal and BMP Signaling by Mutual Signaling Effector Antagonism

Cell Rep. 2020 Apr 7;31(1):107487. doi: 10.1016/j.celrep.2020.03.051.


Opposing sources of bone morphogenetic protein (BMP) and Nodal signaling molecules are sufficient to induce the formation of a full axis in zebrafish embryos. To address how these signals orchestrate patterning, we transplant sources of fluorescently tagged Nodal and BMP into zebrafish embryos, robustly inducing the formation of secondary axes. Nodal and BMP signal non-cell-autonomously and form similar protein gradients in this context, but the signaling range of Nodal (pSmad2) is shorter than the BMP range (pSmad5). This yields a localized region of pSmad2 activity around the Nodal source, overlapping with a broad domain of pSmad5 activity across the embryo. Cell fates induced in various regions stereotypically correlate with pSmad2-to-pSmad5 ratios and can even be induced BMP- and Nodal-independently with different ratios of constitutively active Smad2 and Smad5. Strikingly, we find that Smad2 and Smad5 antagonize each other for specific cell fates, providing a mechanism for how cells integrate and discriminate between overlapping signals during development.

Keywords: BMP; Nodal; Smad2; Smad5; axis induction; development; embryo; gradients; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Bone Morphogenetic Proteins / physiology
  • Cell Lineage / physiology
  • Gene Expression Regulation, Developmental / genetics
  • Nodal Protein / metabolism*
  • Nodal Protein / physiology
  • Signal Transduction / physiology
  • Smad2 Protein / metabolism
  • Smad5 Protein / metabolism
  • Transforming Growth Factor beta / metabolism
  • Zebrafish / embryology*
  • Zebrafish / metabolism
  • Zebrafish Proteins / metabolism


  • Bone Morphogenetic Proteins
  • Nodal Protein
  • Smad2 Protein
  • Smad5 Protein
  • Transforming Growth Factor beta
  • Zebrafish Proteins
  • smad2 protein, zebrafish
  • smad5 protein, zebrafish