Proteolytic Restriction of Chordin Range Underlies BMP Gradient Formation

Tuazon, Francesca B.; Wang, Xu; Andrade, Jonathan Lee; Umulis, David M.; Mullins, Mary C.

doi:10.1016/j.celrep.2020.108039

Cited by 22 publications

(29 citation statements)

References 86 publications

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“…To investigate the spatial shifts in target gene expression when the pSmad5 gradient shape is altered, we used chordin mutant early gastrula embryos. Chordin is a BMP ligand antagonist that acts as a dorsal sink for BMP, thus shaping BMP signaling activity during gastrulation [ 23 , 35 , 63 ]. In chordin mutant embryos, the shape of the BMP signaling gradient is altered where the highest levels of BMP signaling activity expand laterally, and the slope of the gradient is shallower in the lateral regions ( Fig 4C and 4G–4L , S9A Fig ).…”

Section: Resultsmentioning

confidence: 99%

“…Changing the level of BMP signaling across the embryo shifts the position and relative proportion of ventral cell fates, demonstrating that the gradient shape is important for patterning [ 20 , 28 – 32 ]. The shape of the BMP signaling gradient depends on the extracellular antagonist Chordin, which binds the BMP ligand and blocks signaling in the dorsal region of the embryo [ 23 , 28 , 33 – 35 ]. The BMP signaling gradient is dynamic during late blastula to mid-gastrula stages; thus, pSmad5 nuclear levels differ across the embryo both in space and time [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

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The BMP signaling gradient is interpreted through concentration thresholds in dorsal–ventral axial patterning

2021

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Bone Morphogenetic Protein (BMP) patterns the dorsal–ventral (DV) embryonic axis in all vertebrates, but it is unknown how cells along the DV axis interpret and translate the gradient of BMP signaling into differential gene activation that will give rise to distinct cell fates. To determine the mechanism of BMP morphogen interpretation in the zebrafish gastrula, we identified 57 genes that are directly activated by BMP signaling. By using Seurat analysis of single-cell RNA sequencing (scRNA-seq) data, we found that these genes are expressed in at least 3 distinct DV domains of the embryo. We distinguished between 3 models of BMP signal interpretation in which cells activate distinct gene expression through interpretation of thresholds of (1) the BMP signaling gradient slope; (2) the BMP signal duration; or (3) the level of BMP signal activation. We tested these 3 models using quantitative measurements of phosphorylated Smad5 (pSmad5) and by examining the spatial relationship between BMP signaling and activation of different target genes at single-cell resolution across the embryo. We found that BMP signaling gradient slope or BMP exposure duration did not account for the differential target gene expression domains. Instead, we show that cells respond to 3 distinct levels of BMP signaling activity to activate and position target gene expression. Together, we demonstrate that distinct pSmad5 threshold levels activate spatially distinct target genes to pattern the DV axis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The BMP signaling gradient is interpreted through concentration thresholds in dorsal–ventral axial patterning

2021

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“…These results suggested a source-sink mechanism for zebrafish embryo BMP gradient formation that emerges from diffusible BMP ligands and Chordin acting as a dorsal sink for the BMP ligand ( Zinski et al, 2017 ). Further elaborating on this mechanism are a series of recent molecular-genetic experiments showing that the Tolloid/Bmp1a metalloprotease homologs effectively restrict Chordin to dorsal regions, preventing it from diffusing into ventral regions ( Tuazon et al, 2020 ). Directly testing the role of Chordin as a dorsal sink, a membrane-tethered Chordin in a background lacking the metalloproteases and endogenous Chordin was shown, remarkably, to rescue DV patterning ( Tuazon et al, 2020 ).…”

Section: Diversity Of Gradient Formation Mechanisms By Diffusible Regmentioning

confidence: 99%

“…Further elaborating on this mechanism are a series of recent molecular-genetic experiments showing that the Tolloid/Bmp1a metalloprotease homologs effectively restrict Chordin to dorsal regions, preventing it from diffusing into ventral regions ( Tuazon et al, 2020 ). Directly testing the role of Chordin as a dorsal sink, a membrane-tethered Chordin in a background lacking the metalloproteases and endogenous Chordin was shown, remarkably, to rescue DV patterning ( Tuazon et al, 2020 ). Computational modeling of immobile Chordin supports gradient rescue for a large number of solutions that simulate the experiment with localized expression of lateral and dorsal membrane-tethered Chordin ( Tuazon et al, 2020 ).…”

Section: Diversity Of Gradient Formation Mechanisms By Diffusible Regmentioning

confidence: 99%

“…Directly testing the role of Chordin as a dorsal sink, a membrane-tethered Chordin in a background lacking the metalloproteases and endogenous Chordin was shown, remarkably, to rescue DV patterning ( Tuazon et al, 2020 ). Computational modeling of immobile Chordin supports gradient rescue for a large number of solutions that simulate the experiment with localized expression of lateral and dorsal membrane-tethered Chordin ( Tuazon et al, 2020 ).…”

Section: Diversity Of Gradient Formation Mechanisms By Diffusible Regmentioning

confidence: 99%

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Diversity and robustness of bone morphogenetic protein pattern formation

2021

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Pattern formation by bone morphogenetic proteins (BMPs) demonstrates remarkable plasticity and utility in several contexts, such as early embryonic development, tissue patterning and the maintenance of stem cell niches. BMPs pattern tissues over many temporal and spatial scales: BMP gradients as short as 1-2 cell diameters maintain the stem cell niche of the Drosophila germarium over a 24-h cycle, and BMP gradients of several hundred microns establish dorsal-ventral tissue specification in Drosophila, zebrafish and Xenopus embryos in timescales between 30 min and several hours. The mechanisms that shape BMP signaling gradients are also incredibly diverse. Although ligand diffusion plays a dominant role in forming the gradient, a cast of diffusible and non-diffusible regulators modulate gradient formation and confer robustness, including scale invariance and adaptability to perturbations in gene expression and growth. In this Review, we document the diverse ways that BMP gradients are formed and refined, and we identify the core principles that they share to achieve reliable performance.

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Highly conserved and extremely evolvable: BMP signalling in secondary axis patterning of Cnidaria and Bilateria

Mörsdorf,

Knabl,

Genikhovich

2024

Dev Genes Evol

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Bilateria encompass the vast majority of the animal phyla. As the name states, they are bilaterally symmetric, that is with a morphologically clear main body axis connecting their anterior and posterior ends, a second axis running between their dorsal and ventral surfaces, and with a left side being roughly a mirror image of their right side. Bone morphogenetic protein (BMP) signalling has widely conserved functions in the formation and patterning of the second, dorso-ventral (DV) body axis, albeit to different extents in different bilaterian species. Whilst initial findings in the fruit fly Drosophila and the frog Xenopus highlighted similarities amongst these evolutionarily very distant species, more recent analyses featuring other models revealed considerable diversity in the mechanisms underlying dorsoventral patterning. In fact, as phylogenetic sampling becomes broader, we find that this axis patterning system is so evolvable that even its core components can be deployed differently or lost in different model organisms. In this review, we will try to highlight the diversity of ways by which BMP signalling controls bilaterality in different animals, some of which do not belong to Bilateria. Future research combining functional analyses and modelling is bound to give us some understanding as to where the limits to the extent of the evolvability of BMP-dependent axial patterning may lie.

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Proteolytic Restriction of Chordin Range Underlies BMP Gradient Formation

Cited by 22 publications

References 86 publications

The BMP signaling gradient is interpreted through concentration thresholds in dorsal–ventral axial patterning

The BMP signaling gradient is interpreted through concentration thresholds in dorsal–ventral axial patterning

Diversity and robustness of bone morphogenetic protein pattern formation

Highly conserved and extremely evolvable: BMP signalling in secondary axis patterning of Cnidaria and Bilateria

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