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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
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09 Jun 2011
New Finding
DOI: 10.3410/f.11049956.12003054
Why are there so many different proteins and mechanisms by which transforming growth factor (TGF)beta superfamily ligand signalling is regulated? This manuscript provides evidence that many of these regulators are part of a coherent feedback loop that protects cells from environmental fluctuations, effecting...Continue reading
Why are there so many different proteins and mechanisms by which transforming growth factor (TGF)beta superfamily ligand signalling is regulated? This manuscript provides evidence that many of these regulators are part of a coherent feedback loop that protects cells from environmental fluctuations, effecting developmental canalization and increasing the range of ligand concentrations to which cells can respond.
This study examined Bambi, SMAD6 and SMAD7, a bone morphogenetic protein (BMP)4 synexpression group, as part of a negative feedback loop in HEK293 cells and in Xenopus embryos. Bambi was originally identified as a dominant-negative TGFbeta superfamily type I receptor subunit {1}, while SMAD 6 and 7 function inside the cell to abrogate signal transduction. Experimental analyses in transfected cells showed that Bambi expression increases the range of BMP4 signals to which cells can respond. In the context of Xenopus embryos, morpholino oligo knockdown experiments demonstrated that expression of each of these regulators reduces phenotypic variability. Mathematical modeling predicted that the timing and dosage responsiveness to BMP4 would be identical within the synexpression group of genes, a result that was validated using a short-lived enhanced green fluorescent protein (eGFP) reporter. SMURF1, which is not induced by BMP4 but does inhibit BMP4 signalling, was used as a control. These findings make it compelling to now delineate the dynamic expression of TGFbeta superfamily signaling molecules to reveal how negative and feedback regulation generate the potential for cell-specific signaling outcomes in development and in disease.
This study examined Bambi, SMAD6 and SMAD7, a bone morphogenetic protein (BMP)4 synexpression group, as part of a negative feedback loop in HEK293 cells and in Xenopus embryos. Bambi was originally identified as a dominant-negative TGFbeta superfamily type I receptor subunit {1}, while SMAD 6 and 7 function inside the cell to abrogate signal transduction. Experimental analyses in transfected cells showed that Bambi expression increases the range of BMP4 signals to which cells can respond. In the context of Xenopus embryos, morpholino oligo knockdown experiments demonstrated that expression of each of these regulators reduces phenotypic variability. Mathematical modeling predicted that the timing and dosage responsiveness to BMP4 would be identical within the synexpression group of genes, a result that was validated using a short-lived enhanced green fluorescent protein (eGFP) reporter. SMURF1, which is not induced by BMP4 but does inhibit BMP4 signalling, was used as a control. These findings make it compelling to now delineate the dynamic expression of TGFbeta superfamily signaling molecules to reveal how negative and feedback regulation generate the potential for cell-specific signaling outcomes in development and in disease.
References
1.
Silencing of TGF-beta signalling by the pseudoreceptor BAMBI.
Nature 1999 Sep 30; 6752(401):480-5
PMID: 10519551
Disclosures
None declared
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Loveland K: F1000Prime Recommendation of [Paulsen M et al., Proc Natl Acad Sci U S A 2011, 108(25):10202-7]. In F1000Prime, 09 Jun 2011; DOI: 10.3410/f.11049956.12003054. F1000Prime.com/11049956#eval12003054
04 Jul 2011
Jean-François Brunet
F1000 Neuroscience
Institut de Biologie de l’Ecole normale supérieure,
Paris, France.
F1000 Neuroscience
Institut de Biologie de l’Ecole normale supérieure,
Paris, France.
New Finding
DOI: 10.3410/f.11049956.12783054
This paper is a stimulating piece of quantitative biology, combining experimental data and mathematical modeling, on the dynamic properties of bone morphogenetic protein (BMP) signaling during embryogenesis.
It shows, both in vitro (in a cell line) and in vivo (in Xenopus embryos), that the outcome of...Continue reading
It shows, both in vitro (in a cell line) and in vivo (in Xenopus embryos), that the outcome of...Continue reading
This paper is a stimulating piece of quantitative biology, combining experimental data and mathematical modeling, on the dynamic properties of bone morphogenetic protein (BMP) signaling during embryogenesis.
It shows, both in vitro (in a cell line) and in vivo (in Xenopus embryos), that the outcome of BMP4 signaling is made more linear and less variable by a negative feedback from three of its own targets, BAMBI, SMAD6 and SMAD7. The quantitative responsiveness of the inhibitors to the signal they inhibit is essential to the virtues of this molecular machinery. Thus, during evolution of a signaling pathway, the binding properties of proteins were coupled with that of their promoters to optimize its dynamic range and robustness.
It shows, both in vitro (in a cell line) and in vivo (in Xenopus embryos), that the outcome of BMP4 signaling is made more linear and less variable by a negative feedback from three of its own targets, BAMBI, SMAD6 and SMAD7. The quantitative responsiveness of the inhibitors to the signal they inhibit is essential to the virtues of this molecular machinery. Thus, during evolution of a signaling pathway, the binding properties of proteins were coupled with that of their promoters to optimize its dynamic range and robustness.
Disclosures
None declared
Brunet J: F1000Prime Recommendation of [Paulsen M et al., Proc Natl Acad Sci U S A 2011, 108(25):10202-7]. In F1000Prime, 04 Jul 2011; DOI: 10.3410/f.11049956.12783054. F1000Prime.com/11049956#eval12783054
F1000Prime Recommendations, Dissents and Comments for [Paulsen M et al., Proc Natl Acad Sci U S A 2011, 108(25):10202-7]. In F1000Prime, 18 May 2013; F1000Prime.com/11049956
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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.
PMID: 21633009
