Negative feedback in the bone morphogenetic protein 4 (BMP4) synexpression group governs its dynamic signaling range and canalizes development

Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10202-7. doi: 10.1073/pnas.1100179108. Epub 2011 Jun 1.

Abstract

What makes embryogenesis a robust and canalized process is an important question in developmental biology. A bone morphogenetic protein (BMP) morphogen gradient plays a key role in embryonic development, and we are beginning to understand how the self-regulating properties of its signaling circuitry ensure robust embryonic patterning. An unexplored question is why the BMP signaling circuit is organized as a modular synexpression group, with a prevalence of feedback inhibitors. Here, we provide evidence from direct experimentation and mathematical modeling that the synexpressed feedback inhibitors BAMBI, SMAD6, and SMAD7 (i) expand the dynamic BMP signaling range essential for proper embryonic patterning and (ii) reduce interindividual phenotypic and molecular variability in Xenopus embryos. Thereby, negative feedback linearizes signaling responses and confers robust patterning, thus promoting canalized development. The presence of negative feedback inhibitors in other growth factor synexpression groups suggests that these properties may constitute a general principle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning / physiology*
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 4 / metabolism*
  • Feedback, Physiological*
  • Gene Expression Regulation, Developmental*
  • Genes, Reporter
  • HEK293 Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Models, Theoretical
  • Signal Transduction / physiology*
  • Smad6 Protein / genetics
  • Smad6 Protein / metabolism
  • Smad7 Protein / genetics
  • Smad7 Protein / metabolism
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism
  • Xenopus laevis / anatomy & histology
  • Xenopus laevis / embryology
  • Xenopus laevis / genetics
  • Xenopus laevis / metabolism

Substances

  • Bone Morphogenetic Protein 4
  • Membrane Proteins
  • Smad6 Protein
  • Smad6 protein, Xenopus
  • Smad7 Protein
  • Smad7 protein, Xenopus
  • Xenopus Proteins
  • bambi-A protein, Xenopus