scholarly journals Systems biology derived source-sink mechanism of BMP gradient formation

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Joseph Zinski ◽  
Ye Bu ◽  
Xu Wang ◽  
Wei Dou ◽  
David Umulis ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Systems Biology ◽  
Bmp Signaling ◽  
Morphogen Gradient ◽  
Wild Type ◽  
Morphogenetic Protein ◽  
Gradient Formation ◽  
Source Sink ◽  
Bmp Antagonist ◽  
Prevailing View

A morphogen gradient of Bone Morphogenetic Protein (BMP) signaling patterns the dorsoventral embryonic axis of vertebrates and invertebrates. The prevailing view in vertebrates for BMP gradient formation is through a counter-gradient of BMP antagonists, often along with ligand shuttling to generate peak signaling levels. To delineate the mechanism in zebrafish, we precisely quantified the BMP activity gradient in wild-type and mutant embryos and combined these data with a mathematical model-based computational screen to test hypotheses for gradient formation. Our analysis ruled out a BMP shuttling mechanism and a bmp transcriptionally-informed gradient mechanism. Surprisingly, rather than supporting a counter-gradient mechanism, our analyses support a fourth model, a source-sink mechanism, which relies on a restricted BMP antagonist distribution acting as a sink that drives BMP flux dorsally and gradient formation. We measured Bmp2 diffusion and found that it supports the source-sink model, suggesting a new mechanism to shape BMP gradients during development.

Abstract 17763: Inhibition of Bone Morphogenetic Protein Signaling Reduces Endothelial-Mesenchymal Transition and Vascular Smooth Muscle Cell Calcification Associated with Matrix Gla Protein Deficiency

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Megan F Burke ◽  
Caitlin O’Rourke ◽  
Trejeeve Martyn ◽  
Hannah R Shakartzi ◽  
Timothy E Thayer ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Bone Morphogenetic Protein ◽  
Vascular Calcification ◽  
Bmp Signaling ◽  
Matrix Gla Protein ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Morphogenetic Protein ◽  
Endothelial Mesenchymal Transition

Background: Matrix Gla protein (MGP) is an extracellular matrix protein that inhibits bone morphogenetic protein (BMP) signaling in vitro. MGP deficiency induces vascular calcification associated with osteogenic transdifferentiation of endothelial cells (via endothelial-mesenchymal transition, EndMT) and vascular smooth muscle cells (VSMCs). We previously reported that treatment with two pharmacologic inhibitors of BMP signaling reduced aortic calcification in MGP-/- mice. We hypothesized that BMP signaling is essential for EndMT and VSMC osteogenic transdifferentiation induced by MGP deficiency. Methods and Results: Aortic levels of mRNAs encoding markers of osteogenesis (Runx2 and osteopontin) and EndMT (nanog, Sox2, and Oct3/4) were greater in MGP-/- than in wild-type mice (P<0.01 for all). Aortic expression of markers of VSMC differentiation (α-smooth muscle actin, transgelin, and calponin) was less in MGP-/- than in wild-type mice (P<0.001 for all). Treatment of MGP-/- mice with the BMP signaling inhibitor, LDN-193189, reduced expression of both osteogenic and EndMT markers (P<0.05 for all) but did not prevent VSMC de-differentiation. Depletion of MGP in cultured wild-type VSMCs with siRNA specific for MGP (siMGP) was associated with a 30-40% reduction in levels of mRNAs encoding markers of VSMC differentiation (P<0.05 for all), an effect that was not prevented by LDN-193189. Incubation in phosphate-containing media induced greater calcification in siMGP-treated VSMCs than in cells treated with control siRNA (P<0.0001). Treatment with LDN-193189 reduced calcification in siMGP-treated VSMCs (50%, P=0.0003). Conversely, infection of MGP-/- VSMCs with adenovirus specifying MGP increased expression of markers of VSMC differentiation by 60-80% (P<0.01 for all) and decreased calcification by 74% (P=0.03). Conclusions: Inhibition of BMP signaling suppresses osteogenic and EndMT gene programs in MGP-/- mice and reduces calcification of siMGP-treated VSMCs. However, MGP deficiency induces VSMC de-differentiation via a BMP-independent mechanism. These findings suggest that the processes underlying vascular calcification in MGP deficiency are mediated by both BMP signaling-dependent and -independent mechanisms.

scholarly journals Shuttling of Dorsal by Cactus: mechanism and implications

2019 ◽  
Author(s):  
Allison E. Schloop ◽  
Sophia Carrell-Noel ◽  
Gregory T. Reeves
Keyword(s):  
Cell Types ◽  
Bmp Signaling ◽  
Previous Literature ◽  
Drosophila Embryo ◽  
Morphogen Gradient ◽  
Facilitated Diffusion ◽  
Morphogen Gradients ◽  
Binding Partner ◽  
Early Drosophila Embryo ◽  
Gradient Formation

AbstractIn a developing animal, morphogen gradients act to pattern tissues into distinct domains of cell types. However, despite their prevalence in development, morphogen gradient formation is a matter of debate. In our recent publication, we showed that the Dorsal/NF-κB morphogen gradient, which patterns the DV axis of the early Drosophila embryo, is partially established by a mechanism of facilitated diffusion. This mechanism, also known as “shuttling,” occurs when a binding partner of the morphogen facilitates the diffusion of the morphogen, allowing it to accumulate at a given site. In this case, the inhibitor Cactus/IκB facilitates the diffusion of Dorsal/NF-κB. In the fly embryo, we used computation and experiment to not only show that shuttling occurs in the embryo, but also that it enables the viability of embryos that inherit only one copy of dorsal maternally. Here we further discuss our evidence behind the shuttling mechanism, the previous literature data explained by the mechanism, and how it may also be critical for robustness of development. Finally, we describe an interaction between Dorsal and BMP signaling that is likely affected by shuttling.

scholarly journals Scale invariance of BMP signaling gradients in zebrafish

2018 ◽  
Author(s):  
Yan Huang ◽  
David Umulis
Keyword(s):  
Scale Invariance ◽  
Bmp Signaling ◽  
Spatial Patterning ◽  
Protein Signaling ◽  
Wild Type ◽  
Bone Morphogenetic Protein Signaling ◽  
Cross Sectional ◽  
Morphogenetic Protein ◽  
Core Questions ◽  
Gradient Scaling

In both vertebrates and invertebrates, spatial patterning along the Dorsal-ventral (DV) embryonic axis depends on a morphogen gradient of Bone Morphogenetic Protein signaling. Scale invariance of DV patterning by BMPs has been found in both vertebrates and invertebrates, however the mechanisms that regulate gradient scaling remain controversial. To obtain quantitative data that can be used to address core questions of scaling, we introduce a method to tune the size of zebrafish embryos by reducing varying amounts of vegetal yolk. We quantified the BMP signaling gradient in wild-type and perturbed embryos and found that the system scales for reductions in cross-sectional perimeter of up to 30%. Furthermore, we found that the degree of scaling for intraspecies scaling within zebrafish is greater than that between Danioninae species.

scholarly journals Patterning and growth control in vivo by an engineered GFP gradient

Science ◽  
2020 ◽  
Vol 370 (6514) ◽  
pp. 321-327 ◽  
Author(s):  
Kristina S. Stapornwongkul ◽  
Marc de Gennes ◽  
Luca Cocconi ◽  
Guillaume Salbreux ◽  
Jean-Paul Vincent
Keyword(s):  
Fluorescent Protein ◽  
Growth Control ◽  
Positional Information ◽  
Morphogen Gradient ◽  
Length Scale ◽  
Wild Type ◽  
Morphogen Gradients ◽  
Gradient Formation ◽  
Green Fluorescent

Morphogen gradients provide positional information during development. To uncover the minimal requirements for morphogen gradient formation, we have engineered a synthetic morphogen in Drosophila wing primordia. We show that an inert protein, green fluorescent protein (GFP), can form a detectable diffusion-based gradient in the presence of surface-associated anti-GFP nanobodies, which modulate the gradient by trapping the ligand and limiting leakage from the tissue. We next fused anti-GFP nanobodies to the receptors of Dpp, a natural morphogen, to render them responsive to extracellular GFP. In the presence of these engineered receptors, GFP could replace Dpp to organize patterning and growth in vivo. Concomitant expression of glycosylphosphatidylinositol (GPI)–anchored nonsignaling receptors further improved patterning, to near–wild-type quality. Theoretical arguments suggest that GPI anchorage could be important for these receptors to expand the gradient length scale while at the same time reducing leakage.

scholarly journals The BMP signaling pathway is required together with the FGF pathway for notochord induction in the ascidian embryo

Development ◽  
2001 ◽  
Vol 128 (14) ◽  
pp. 2629-2638 ◽  
Author(s):  
Sébastien Darras ◽  
Hiroki Nishida
Keyword(s):  
Time Window ◽  
Bmp Signaling ◽  
Cell Stage ◽  
Morphogenetic Protein ◽  
Positive Target ◽  
Bmp Pathway ◽  
Notochord Cells ◽  
Bmp Antagonist ◽  
Ascidian Embryo

The 40 notochord cells of the ascidian tadpole invariably arise from two different lineages: the primary (A-line) and the secondary (B-line) lineages. It has been shown that the primary notochord cells are induced by presumptive endoderm blastomeres between the 24-cell and the 64-cell stage. Signaling through the fibroblast growth factor (FGF) pathway is required for this induction. We have investigated the role of the bone morphogenetic protein (BMP) pathway in ascidian notochord formation. HrBMPb (the ascidian BMP2/4 homologue) is expressed in the anterior endoderm at the 44-cell stage before the completion of notochord induction. The BMP antagonist Hrchordin is expressed in a complementary manner in all surrounding blastomeres and appears to be a positive target of the BMP pathway. Unexpectedly, chordin overexpression reduced formation of both primary and secondary notochord. Conversely, primary notochord precursors isolated prior to induction formed notochord in presence of BMP-4 protein. While bFGF protein had a similar activity, notochord precursors showed a different time window of competence to respond to BMP-4 and bFGF. Our data are consistent with bFGF acting from the 24-cell stage, while BMP-4 acts during the 44-cell stage. However, active FGF signaling was also required for induction by BMP-4. In the secondary lineage, notochord specification also required two inducing signals: an FGF signal from anterior and posterior endoderm from the 24-cell stage and a BMP signal from anterior endoderm during the 44-cell stage.

BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb

Development ◽  
2001 ◽  
Vol 128 (22) ◽  
pp. 4463-4474 ◽  
Author(s):  
Sandrine Pizette ◽  
Cory Abate-Shen ◽  
Lee Niswander
Keyword(s):  
Apical Ectodermal Ridge ◽  
Bmp Signaling ◽  
Signal Loss ◽  
Dorsoventral Patterning ◽  
Morphogenetic Protein ◽  
Vertebrate Limb ◽  
Common Signal ◽  
Necessary And Sufficient ◽  
Bmp Antagonist ◽  
Dorsal Pattern

Dorsoventral (DV) patterning of the vertebrate limb requires the function of the transcription factor Engrailed 1 (EN1) in the ventral ectoderm. EN1 restricts, to the dorsal half of the limb, the expression of the two genes known to specify dorsal pattern. Limb growth along the proximodistal (PD) axis is controlled by the apical ectodermal ridge (AER), a specialized epithelium that forms at the distal junction between dorsal and ventral ectoderm. Using retroviral-mediated misexpression of the bone morphogenetic protein (BMP) antagonist Noggin or an activated form of the BMP receptor in the chick limb, we demonstrate that BMP plays a key role in both DV patterning and AER induction. Thus, the DV and PD axes are linked by a common signal. Loss and gain of BMP function experiments show that BMP signaling is both necessary and sufficient to regulate EN1 expression, and consequently DV patterning. Our results also indicate that BMPs are required during induction of the AER. Manipulation of BMP signaling results in either disruptions in the endogenous AER, leading to absent or severely truncated limbs or the formation of ectopic AERs that can direct outgrowth. Moreover, BMP controls the expression of the MSX transcription factors, and our results suggest that MSX acts downstream of BMP in AER induction. We propose that the BMP signal bifurcates at the level of EN1 and MSX to mediate differentially DV patterning and AER induction, respectively.

scholarly journals Author response: Systems biology derived source-sink mechanism of BMP gradient formation

2017 ◽  
Author(s):  
Joseph Zinski ◽  
Ye Bu ◽  
Xu Wang ◽  
Wei Dou ◽  
David Umulis ◽  
...  
Keyword(s):  
Systems Biology ◽  
Author Response ◽  
Gradient Formation ◽  
Response Systems ◽  
Source Sink

scholarly journals The BMP antagonist Gremlin1 contributes to the development of cortical excitatory neurons, motor balance and fear responses

Development ◽  
2021 ◽  
Author(s):  
Mari Ichinose ◽  
Nobumi Suzuki ◽  
Tongtong Wang ◽  
Hiroki Kobayashi ◽  
Laura Vrbanac ◽  
...  
Keyword(s):  
Lineage Tracing ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Embryonic Mouse ◽  
Glutamatergic Neurons ◽  
Functional Maturation ◽  
Morphogenetic Protein ◽  
Dorsal Telencephalon ◽  
Endogenous Modulators ◽  
Bmp Antagonist

Bone morphogenetic protein (BMP) signaling is required for early forebrain development and cortical formation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Here we show that expression of the BMP antagonist, Grem1, marks committed layer Ⅴ and Ⅵ glutamatergic neurons in the embryonic mouse brain. Lineage tracing of Grem1-expressing cells in the embryonic brain was examined by administration of tamoxifen to pregnant Grem1creERT; Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc, bulk mRNA seq analysis of differentially expressed transcripts between FACS sorted Grem1 positive and negative cells was performed. We also generated Emx1-cre mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox) in which the Grem1 gene was deleted specifically in the dorsal telencephalon. Grem1Emx1cKO animals had reduced cortical thickness, especially layers Ⅴ and Ⅵ and impaired motor balance and fear sensitivity compared to littermate controls. This study has revealed new roles for Grem1 in the structural and functional maturation of the developing cortex.

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