Scaling of the BMP activation gradient in Xenopus embryos

Ben‐Zvi, Danny; Shilo, Ben‐Zion; Fainsod, Abraham; Barkai, Naama

doi:10.1038/nature07059

Cited by 219 publications

(284 citation statements)

References 48 publications

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“…A shuttling-based mechanism of BMP transport is also used in a number of other developmental contexts, including the early vertebrate embryo (24), specification of the vertebral field in mice (25), and establishment of the posterior cross-vein territory in the Drosophila wing disk (26,27). Restriction of BMP movement may also be important in other contexts, including several where collagen IV was already shown to regulate a shortrange Dpp signal, such as the ovarian stem cell niche and the tip of malpighian tubules (8,28).…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…Although it activates the competing BMP pathway, we found BMP2 to be upregulated in the GSC-GFP þ cells. This may correlate with its expression, together with antidorsalizing morphogenic protein (ADMP), at the Xenopus organizer, where it seems to have a role in limiting organizer expansion [34][35][36]. The genes upregulated in the GSC-GFP À cells represent a more heterogeneous population, as they cannot be attributed to any particular known cell type (Fig.…”

Section: Transcriptome Analysis Of Gsc 1 Cells Derived From Differentmentioning

confidence: 99%

Molecular and Functional Characterizations of Gastrula Organizer Cells Derived from Human Embryonic Stem Cells

et al. 2011

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The Spemann-Mangold organizer is the structure that provides the signals, which initiate pattern formation in the developing vertebrate embryo, affecting the main body axes. Very little is known about axial induction in the gastrulating human embryo, as research is hindered by obvious ethical restrictions. Human embryonic stem cells (hESCs) are pluripotent cells derived from the pregastrula embryo that can differentiate in culture following a program similar to normal embryonic development but without pattern formation. Here, we show that in hESC-derived embryoid bodies, we can induce differentiation of cells that harbor markers and characteristics of the gastrula-organizer. Moreover, genetic labeling of these cells enabled their purification, and the discovery of a comprehensive set of their secreted proteins, cell surface receptors, and nuclear factors characteristic of the organizer. Remarkably, transplantation of cell populations enriched for the putative human organizer into frog embryos induced a secondary axis. Our research demonstrates that the human organizer can be induced in vitro and paves the way for the study of pattern formation and the initial regulation of body axis establishment in humans.

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“…In a similar way, Chordin and CV2, or Crescent and Sizzled, which are under reciprocal transcriptional regulation, compensate for the loss of each other (33,35). Embryological experiments and mathematical modeling in Xenopus have led to the proposal that a D-V flux of BMPs bound to Chordin may increase the robustness of the self-organizing Chordin-BMPTolloid extracellular pathway (8,31,36). However, none of the endogenous proteins of this morphogen pathway have ever been directly visualized in vertebrate embryos.…”

Section: Significancementioning

confidence: 99%

Chordin forms a self-organizing morphogen gradient in the extracellular space between ectoderm and mesoderm in the Xenopus embryo

Plouhinec

Zakin

Moriyama

et al. 2013

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

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The vertebrate body plan follows stereotypical dorsal-ventral (D-V) tissue differentiation controlled by bone morphogenetic proteins (BMPs) and secreted BMP antagonists, such as Chordin. The three germ layers-ectoderm, mesoderm, and endoderm-are affected coordinately by the Chordin-BMP morphogen system. However, extracellular morphogen gradients of endogenous proteins have not been directly visualized in vertebrate embryos to date. In this study, we improved immunolocalization methods in Xenopus embryos and analyzed the distribution of endogenous Chordin using a specific antibody. Chordin protein secreted by the dorsal Spemann organizer was found to diffuse along a narrow region that separates the ectoderm from the anterior endoderm and mesoderm. This Fibronectin-rich extracellular matrix is called "Brachet's cleft" in the Xenopus gastrula and is present in all vertebrate embryos. Chordin protein formed a smooth gradient that encircled the embryo, reaching the ventral-most Brachet cleft. Depletion with morpholino oligos showed that this extracellular gradient was regulated by the Chordin protease Tolloid and its inhibitor Sizzled. The Chordin gradient, as well as the BMP signaling gradient, was self-regulating and, importantly, was able to rescale in dorsal half-embryos. Transplantation of Spemann organizer tissue showed that Chordin diffused over long distances along this signaling highway between the ectoderm and mesoderm. Chordin protein must reach very high concentrations in this narrow region. We suggest that as ectoderm and mesoderm undergo morphogenetic movements during gastrulation, cells in both germ layers read their positional information coordinately from a single morphogen gradient located in Brachet's cleft.

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Scaling of the BMP activation gradient in Xenopus embryos

Cited by 219 publications

References 48 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

Molecular and Functional Characterizations of Gastrula Organizer Cells Derived from Human Embryonic Stem Cells

Chordin forms a self-organizing morphogen gradient in the extracellular space between ectoderm and mesoderm in the Xenopus embryo

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