title: Negative feedback in the bone morphogenetic protein 4 (BMP4) synexpression group governs its dynamic signaling range and canalizes development.
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.
authors.affiliation: Division of Molecular Embryology and Department of Theoretical Bioinformatics, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Paulsen
authors.forename: Stefan
authors.initials: S
authors.lastname: Legewie
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Emil
authors.initials: E
authors.lastname: Karaulanov
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008962:Models, Theoretical; D015398:Signal Transduction / Q000502:physiology*; D051905:Smad6 Protein / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000033:anatomy & histology / Q000196:embryology / Q000235:genetics / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D008565:Membrane Proteins; D051905:Smad6 Protein; C497805:Smad6 protein, Xenopus; D051906:Smad7 Protein; C497809:Smad7 protein, Xenopus; D029867:Xenopus Proteins; C121859:bambi-A protein, Xenopus