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Proc Natl Acad Sci U S A
2011 Jun 21;10825:10202-7. doi: 10.1073/pnas.1100179108.
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Negative feedback in the bone morphogenetic protein 4 (BMP4) synexpression group governs its dynamic signaling range and canalizes development.
Paulsen M
,
Legewie S
,
Eils R
,
Karaulanov E
,
Niehrs C
.
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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.
Fig. 4. Bambi and smad6/7 negative feedback canalize development. (A) Phenotypes of stage-36/7 X. laevis embryos injected with the indicated MOs. (B) (Upper) Representative body and tail length of stage-36/7 X. laevis embryos injected with MOs as in A. (Lower) Average coefficient of variation of body and tail length of stage 36/7 X. laevis embryos injected as indicated in A of (n = 3) biological replicates with 15–30 embryos per replicate. (C) Eye morphology of stage-36/7 tadpoles from embryos injected as indicated. (D) Quantification of the relative eye size. Graph shows average eye area (Left) and coefficient of variation (Right) of three biological replicates with 15–30 embryos per replicate. (E) qPCR expression analysis of the indicated genes from individual X. laevis embryos of stage 10.5, which were injected at the four-cell stage with the indicated MOs (n = 9–10 embryos per sample). (F) Coefficient of variation of early BMP4 marker gene expression from individual stage 10.5 X. laevis embryos as in C (n = 2). Error bars, SD; *P < 0.05 and **P < 0.01 (unpaired t test).
Fig. S1. The Xenopus laevis BMP4 synexpression group. (A) Schematic model of the Xenopus laevis BMP4 synexpression group embedded into the BMP4/7 signal transduction pathway. Members of the BMP4 synexpression group are drawn in red while non- synexpressed pathway components are in yellow. (B) In situ hybridization of bmp4 and synexpression group members ventx2, bambi, and smad7 in tailbud stage X. laevis embryos; dorsal eye (de), heart field (he), proctodeum (pr). The figure is partially reproduced and adapted from (1) with permission of EMBO Journal.
Fig. S8. Bambi knock down increases variability of the myf5 expression domain width. (A) In situ hybridization of myf5 in midgastrula X. laevis embryos injected equatorially with either 40ng control, 40ng BAMBI MO, or 20/20ng Chordin/Noggin MOs per embryo equatorially at the 2-4 cells stage. (B) Morphometric analysis of myf5 expression domain- width of embryos injected with MOs as in (A). Error bars indicate s.d.; gray boxes represent 50-percentile spread; (AU) arbitrary units; Coefficient of variation (COV).
Ambrosio,
Crossveinless-2 Is a BMP feedback inhibitor that binds Chordin/BMP to regulate Xenopus embryonic patterning.
2008, Pubmed,
Xenbase
Ambrosio,
Crossveinless-2 Is a BMP feedback inhibitor that binds Chordin/BMP to regulate Xenopus embryonic patterning.
2008,
Pubmed
,
Xenbase
Barkai,
Variability and robustness in biomolecular systems.
2007,
Pubmed
Beck,
The role of BMP signaling in outgrowth and patterning of the Xenopus tail bud.
2001,
Pubmed
,
Xenbase
Becskei,
Engineering stability in gene networks by autoregulation.
2000,
Pubmed
Ben-Zvi,
Scaling of the BMP activation gradient in Xenopus embryos.
2008,
Pubmed
,
Xenbase
Bénazet,
A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning.
2009,
Pubmed
Casellas,
Xenopus Smad7 inhibits both the activin and BMP pathways and acts as a neural inducer.
1998,
Pubmed
,
Xenbase
Chen,
The TGF-beta pseudoreceptor gene Bambi is dispensable for mouse embryonic development and postnatal survival.
2007,
Pubmed
,
Xenbase
De Robertis,
Dorsal-ventral patterning and neural induction in Xenopus embryos.
2004,
Pubmed
,
Xenbase
Dosch,
Bmp-4 acts as a morphogen in dorsoventral mesoderm patterning in Xenopus.
1997,
Pubmed
,
Xenbase
Eldar,
Robustness of the BMP morphogen gradient in Drosophila embryonic patterning.
2002,
Pubmed
Eldar,
Self-enhanced ligand degradation underlies robustness of morphogen gradients.
2003,
Pubmed
Galvin,
A role for smad6 in development and homeostasis of the cardiovascular system.
2000,
Pubmed
Gawantka,
Antagonizing the Spemann organizer: role of the homeobox gene Xvent-1.
1995,
Pubmed
,
Xenbase
Gawantka,
Gene expression screening in Xenopus identifies molecular pathways, predicts gene function and provides a global view of embryonic patterning.
1998,
Pubmed
,
Xenbase
Goldman,
Genetic interaction between Bmp2 and Bmp4 reveals shared functions during multiple aspects of mouse organogenesis.
2009,
Pubmed
Gont,
Tail formation as a continuation of gastrulation: the multiple cell populations of the Xenopus tailbud derive from the late blastopore lip.
1993,
Pubmed
,
Xenbase
Gregor,
Probing the limits to positional information.
2007,
Pubmed
Gurdon,
Single cells can sense their position in a morphogen gradient.
1999,
Pubmed
,
Xenbase
Hassler,
Kremen is required for neural crest induction in Xenopus and promotes LRP6-mediated Wnt signaling.
2007,
Pubmed
,
Xenbase
Hata,
OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways.
2000,
Pubmed
,
Xenbase
Hornung,
Noise propagation and signaling sensitivity in biological networks: a role for positive feedback.
2008,
Pubmed
Houchmandzadeh,
Establishment of developmental precision and proportions in the early Drosophila embryo.
2002,
Pubmed
Imamura,
Smad6 inhibits signalling by the TGF-beta superfamily.
1997,
Pubmed
Ishida,
Smad6 is a Smad1/5-induced smad inhibitor. Characterization of bone morphogenetic protein-responsive element in the mouse Smad6 promoter.
2000,
Pubmed
Karaulanov,
Transcriptional regulation of BMP4 synexpression in transgenic Xenopus.
2004,
Pubmed
,
Xenbase
Kiel,
Engineering signal transduction pathways.
2010,
Pubmed
Kuroda,
Neural induction in Xenopus: requirement for ectodermal and endomesodermal signals via Chordin, Noggin, beta-Catenin, and Cerberus.
2004,
Pubmed
,
Xenbase
Lee,
Embryonic dorsal-ventral signaling: secreted frizzled-related proteins as inhibitors of tolloid proteinases.
2006,
Pubmed
,
Xenbase
Legewie,
Recurrent design patterns in the feedback regulation of the mammalian signalling network.
2008,
Pubmed
Li,
Deletion of exon I of SMAD7 in mice results in altered B cell responses.
2006,
Pubmed
Li,
A microRNA imparts robustness against environmental fluctuation during development.
2009,
Pubmed
Lin,
Synergistic activity of Sef and Sprouty proteins in regulating the expression of Gbx2 in the mid-hindbrain region.
2005,
Pubmed
Nakao,
Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling.
1997,
Pubmed
,
Xenbase
Niehrs,
Synexpression groups in eukaryotes.
1999,
Pubmed
,
Xenbase
Oelgeschläger,
The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signalling.
2000,
Pubmed
,
Xenbase
Onichtchouk,
Silencing of TGF-beta signalling by the pseudoreceptor BAMBI.
1999,
Pubmed
,
Xenbase
Phng,
Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis.
2009,
Pubmed
Reversade,
Regulation of ADMP and BMP2/4/7 at opposite embryonic poles generates a self-regulating morphogenetic field.
2005,
Pubmed
,
Xenbase
Shapira,
A role for the homeobox gene Xvex-1 as part of the BMP-4 ventral signaling pathway.
1999,
Pubmed
,
Xenbase
Sigal,
Variability and memory of protein levels in human cells.
2006,
Pubmed
Stelling,
Robustness of cellular functions.
2004,
Pubmed
Tramullas,
BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) reveals the involvement of the transforming growth factor-beta family in pain modulation.
2010,
Pubmed
Ueda,
System-level identification of transcriptional circuits underlying mammalian circadian clocks.
2005,
Pubmed
Yu,
Negative feedback that improves information transmission in yeast signalling.
2008,
Pubmed
Zhu,
A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation.
1999,
Pubmed
,
Xenbase
