Robustness of the BMP morphogen gradient in Drosophila embryonic patterning

Eldar, Avigdor; Dorfman, Ruslan; Weiss, Daniel; Ashe, Hilary L.; Shilo, Ben‐Zion; Barkai, Naama

doi:10.1038/nature01061

Cited by 440 publications

(497 citation statements)

References 23 publications

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“…4G). As shown (7,17), misexpression of wild-type Dpp under the even-skipped stripe 2(st2)-enhancer activates BMP signaling in cells within and outside the stripe, leading to expanded Race expression (Fig. 4H), consistent with the ability of the Dpp/Scw heterodimer to move long-range in the early embryo.…”

Section: Resultsmentioning

confidence: 68%

“…Although the two BMP ligands, Dpp and Scw, are broadly expressed, a conserved set of extracellular regulators mediate the redistribution of the Dpp/Scw heterodimer to the dorsal midline, where peak signaling occurs (4). In dorsal regions, Dpp and Scw are bound by Sog and Tsg into an inhibitory shuttling complex that is unable to bind to receptors but is capable of moving (5)(6)(7)(8)(9). Dpp/Scw is released from the shuttling complex by the protease Tolloid, which cleaves and inactivates Sog (10).…”

mentioning

confidence: 99%

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Multistep molecular mechanism for Bone morphogenetic protein extracellular transport in the Drosophila embryo

Sawala

Sutcliffe

Ashe

2012

Proc. Natl. Acad. Sci. U.S.A.

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In the Drosophila embryo, formation of a bone morphogenetic protein (BMP) morphogen gradient requires transport of a heterodimer of the BMPs Decapentaplegic (Dpp) and Screw (Scw) in a protein shuttling complex. Although the core components of the shuttling complex-Short Gastrulation (Sog) and Twisted Gastrulation (Tsg)-have been identified, key aspects of this shuttling system remain mechanistically unresolved. Recently, we discovered that the extracellular matrix protein collagen IV is important for BMP gradient formation. Here, we formulate a molecular mechanism of BMP shuttling that is catalyzed by collagen IV. We show that Dpp is the only BMP ligand in Drosophila that binds collagen IV. A collagen IV binding-deficient Dpp mutant signals at longer range in vivo, indicating that collagen IV functions to immobilize free Dpp in the embryo. We also provide in vivo evidence that collagen IV functions as a scaffold to promote shuttling complex assembly in a multistep process. After binding of Dpp/ Scw and Sog to collagen IV, protein interactions are remodeled, generating an intermediate complex in which Dpp/Scw-Sog is poised for release by Tsg through specific disruption of a collagen IV-Sog interaction. Because all components are evolutionarily conserved, we propose that regulation of BMP shuttling and immobilization through extracellular matrix interactions is widely used, both during development and in tissue homeostasis, to achieve a precise extracellular BMP distribution.

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Section: Resultsmentioning

confidence: 68%

mentioning

confidence: 99%

Multistep molecular mechanism for Bone morphogenetic protein extracellular transport in the Drosophila embryo

Sawala

Sutcliffe

Ashe

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…This analysis also provides an explanation for the extraordinary robustness (Eldar et al, 2002;England and Cardy, 2005;Houchmandzadeh et al, 2005;Mizutani et al, 2005) of the left-right system. Under normal conditions, less than 1% of frog embryos has any laterality defect, and this proportion is stable against a large number of pharmacological, physiological, and surgical manipulations (Nascone and Mercola, 1997;Levin et al, 2002).…”

Section: Discussionmentioning

confidence: 78%

Mathematical model of morphogen electrophoresis through gap junctions

Esser

Smith

Weaver

et al. 2006

Developmental Dynamics

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Gap junctional communication is important for embryonic morphogenesis. However, the factors regulating the spatial properties of small molecule signal flows through gap junctions remain poorly understood. Recent data on gap junctions, ion transporters, and serotonin during left-right patterning suggest a specific model: the net unidirectional transfer of small molecules through long-range gap junctional paths driven by an electrophoretic mechanism. However, this concept has only been discussed qualitatively, and it is not known whether such a mechanism can actually establish a gradient within physiological constraints. We review the existing functional data and develop a mathematical model of the flow of serotonin through the early Xenopus embryo under an electrophoretic force generated by ion pumps. Through computer simulation of this process using realistic parameters, we explored quantitatively the dynamics of morphogen movement through gap junctions, confirming the plausibility of the proposed electrophoretic mechanism, which generates a considerable gradient in the available time frame. The model made several testable predictions and revealed properties of robustness, cellular gradients of serotonin, and the dependence of the gradient on several developmental constants. This work quantitatively supports the plausibility of electrophoretic control of morphogen movement through gap junctions during early left-right patterning. This conceptual framework for modeling gap junctional signaling-an epigenetic patterning mechanism of wide relevance in biological regulation-suggests numerous experimental approaches in other patterning systems.

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“…Initial characterization of the prototype CR proteins Chordin and Short gastrulation (Sog) revealed inhibition of BMP and Decapentaplegic (Dpp) signaling during axis formation in frogs and flies, respectively. More recently, however, sog was shown to limit dpp activity, in cooperation with twisted gastrulation, and to allow diffusion of a latent complex that can be activated by tolloid (4,20,21). These modifiers thus transform a gradient of ligand into a stepwise response with a distinct boundary of Smad activation.…”

Section: Discussionmentioning

confidence: 99%

The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor β/Activin Signaling in Renal Epithelia

Lin¹,

Patel

Wang³

et al. 2006

Molecular and Cellular Biology

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The transforming growth factor ␤ (TGF-␤) superfamily, including the bone morphogenetic protein (BMP) and TGF-␤/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-␤ but inhibited by BMP7. In this report, the effects of KCP on TGF-␤/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A-and TGF-␤1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-␤1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-␤ and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-␤ activation indicates a critical role for KCP in modulating the responses between these antiand profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.The transforming growth factor ␤ (TGF-␤) superfamily encodes growth and differentiation factors that regulate a wide variety of cellular processes. The members of the TGF-␤ superfamily include two major branches, bone morphogenetic proteins (BMPs) and TGF-␤s/activins (19). TGF-␤ signaling is initiated by the binding of the ligand to a specific pair of type I and type II transmembrane receptors, leading to the phosphorylation of the cytoplasmic serine/threonine kinase domains (19,25). The type I receptors, also known as activinlinked kinases (ALKs), then transduce signals downstream by phosphorylation of receptor-activated Smad proteins. The Smad family can be divided into three distinct subfamilies: receptor-activated Smads (R-Smad), common-partner Smads (Co-Smad), and inhibitory Smads. Whereas Smad1, Smad5, and Smad8 are phosphorylated by BMP type I receptors (ALK-2, ALK-3, and ALK-6), Smad2 and Smad3 are activated by TGF-␤ and activin type I receptors (ALK-5 and ALK-4). The R-Smad and the Co-Smad (Smad4) form a heterooligomer which translocates into the nucleus and regulates expression of ligand-responsive genes. Inhibitory Smads include Smad6 and Smad7, which prevent the activation of R-and Co-Smad.While members of the TGF-␤ superfamily use similar mechanisms to signal to the nucleus, the two major branches achieve specificity by using different elements. Outside the cell, each ligand of the TGF-␤ superfamily binds to specific pairs of the recept...

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Robustness of the BMP morphogen gradient in Drosophila embryonic patterning

Cited by 440 publications

References 23 publications

Multistep molecular mechanism for Bone morphogenetic protein extracellular transport in the Drosophila embryo

Multistep molecular mechanism for Bone morphogenetic protein extracellular transport in the Drosophila embryo

Mathematical model of morphogen electrophoresis through gap junctions

The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor β/Activin Signaling in Renal Epithelia

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