Concentration-dependent patterning of the Xenopus ectoderm by BMP4 and its signal transducer Smad1

Development ◽  
1997 ◽  
Vol 124 (16) ◽  
pp. 3177-3184 ◽  
Author(s):  
P.A. Wilson ◽  
G. Lagna ◽  
A. Suzuki ◽  
A. Hemmati-Brivanlou
Keyword(s):  
Cellular Response ◽  
Organizer Region ◽  
Cell Communication ◽  
Cell Types ◽  
Wing Disc ◽  
Bmp Signaling ◽  
Cell Fates ◽  
Morphogenetic Protein ◽  
Low Concentrations ◽  
Drosophila Protein

Morphogens are thought to establish pattern in early embryos by specifying several cell fates along a gradient of concentration; a well-studied example is the Drosophila protein decapentaplegic (DPP) acting in the wing disc. Recent work has established that bone morphogenetic protein 4 (BMP4), the vertebrate homologue of DPP, controls the fundamental choice between neural and epidermal fates in the vertebrate ectoderm, under the control of antagonists secreted by the organizer region of the mesoderm. We now show that BMP4 can act as a morphogen, evoking distinct responses in Xenopus ectodermal cells at high and low concentrations, in a pattern consistent with the positions of the corresponding cell types in the embryo. Moreover, this complex cellular response to extracellular BMP4 concentration does not require subsequent cell-cell communication and is thus direct, as required of a classical morphogen. We also show that the same series of cell types--epidermis, cement gland and neural tissue--can be produced by progressively inhibiting endogenous BMP signaling with specific antagonists, including the organizer factor noggin. Finally, expression of increasing doses of the signal transduction molecule Smad1 accurately reproduces the response to BMP4 protein. Since Smads have been shown to act in the nucleus, this finding implies a direct translation of extracellular morphogen concentration into transcription factor activity. We propose that a graded distribution of BMP activity controls the specification of several cell types in the gastrula ectoderm and that this extracellular gradient acts by establishing an intracellular and then nuclear gradient of Smad activity.

Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development

Development ◽  
1999 ◽  
Vol 126 (18) ◽  
pp. 4005-4015 ◽  
Author(s):  
M. Weaver ◽  
J.M. Yingling ◽  
N.R. Dunn ◽  
S. Bellusci ◽  
B.L. Hogan
Keyword(s):  
Cell Types ◽  
Surfactant Protein ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Clara Cell ◽  
Mouse Lung ◽  
Marker Genes ◽  
Distal Marker ◽  
Morphogenetic Protein

In the mature mouse lung, the proximal-distal (P-D) axis is delineated by two distinct epithelial subpopulations: the proximal bronchiolar epithelium and the distal respiratory epithelium. Little is known about the signaling molecules that pattern the lung along the P-D axis. One candidate is Bone Morphogenetic Protein 4 (Bmp4), which is expressed in a dynamic pattern in the epithelial cells in the tips of growing lung buds. Previous studies in which Bmp4 was overexpressed in the lung endoderm (Bellusci, S., Henderson, R., Winnier, G., Oikawa, T. and Hogan, B. L. M. (1996) Development 122, 1693–1702) suggested that this factor plays an important role in lung morphogenesis. To further investigate this question, two complementary approaches were utilized to inhibit Bmp signaling in vivo. The Bmp antagonist Xnoggin and, independently, a dominant negative Bmp receptor (dnAlk6), were overexpressed using the surfactant protein C (Sp-C) promoter/enhancer. Inhibiting Bmp signaling results in a severe reduction in distal epithelial cell types and a concurrent increase in proximal cell types, as indicated by morphology and expression of marker genes, including the proximally expressed hepatocyte nuclear factor/forkhead homologue 4 (Hfh4) and Clara cell marker CC10, and the distal marker Sp-C. In addition, electron microscopy demonstrates the presence of ciliated cells, a proximal cell type, in the most peripheral regions of the transgenic lungs. We propose a model in which Bmp4 is a component of an apical signaling center controlling P-D patterning. Endodermal cells at the periphery of the lung, which are exposed to high levels of Bmp4, maintain or adopt a distal character, while cells receiving little or no Bmp4 signal initiate a proximal differentiation program.

scholarly journals Cytonemes in Tumourigenesis

2019 ◽  
Author(s):  
Marta Portela
Keyword(s):  
Cancer Progression ◽  
Tumour Progression ◽  
Cell Signalling ◽  
Cell Communication ◽  
Cell Types ◽  
Wing Disc ◽  
Genetic Ablation ◽  
The Past ◽  
Tumoral Cell ◽  
To Receive

Increasing evidence during the past two decades shows that cells interconnect and communicate through cytonemes. These cytoskeleton-driven extensions of specialized membrane territories have emerged as a novel alternative for cell to cell communication that are involved in development, physiology, and disease. Several recent studies have shown that signalling pathways mediated by cytonemes during development, are essential for certain tumoral cell types progression. In Drosophila wing disc EGFR and RET tumour models, cytoneme formation is required to receive signals from the neighbouring cells. Genetic ablation of cytonemes prevents tumour progression, restores apico-basal polarity, and improves survival. Furthermore, cytonemes in the Drosophila glial cells are essential for glioblastoma progression as they alter Wg/Fz1 signalling between glia and neurons. Research on cytoneme formation, maintenance, and cell signalling mechanisms will help to better understand not only physiological developmental processes and tissue homeostasis but also cancer progression.

scholarly journals Ligand-receptor promiscuity enables cellular addressing

2020 ◽  
Author(s):  
Christina J. Su ◽  
Arvind Murugan ◽  
James M. Linton ◽  
Akshay Yeluri ◽  
Justin Bois ◽  
...  
Keyword(s):  
Cell Fate ◽  
Control Cell ◽  
Cell Communication ◽  
Biochemical Parameter ◽  
Cell Types ◽  
Receptor Expression ◽  
Modeling Framework ◽  
Morphogenetic Protein ◽  
Bmp Pathway ◽  
Fate Decision

AbstractIn multicellular organisms, secreted ligands selectively activate, or “address,” specific target cell populations to control cell fate decision-making and other processes. Key cell-cell communication pathways use multiple promiscuously interacting ligands and receptors, provoking the question of how addressing specificity can emerge from molecular promiscuity. To investigate this issue, we developed a general mathematical modeling framework based on the bone morphogenetic protein (BMP) pathway architecture. We find that promiscuously interacting ligand-receptor systems allow a small number of ligands, acting in combinations, to address a larger number of individual cell types, each defined by its receptor expression profile. Promiscuous systems outperform seemingly more specific one-to-one signaling architectures in addressing capacity. Combinatorial addressing extends to groups of cell types, is robust to receptor expression noise, grows more powerful with increasing receptor multiplicity, and is maximized by specific biochemical parameter relationships. Together, these results identify fundamental design principles governing cell addressing by ligand combinations.

scholarly journals Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling

2021 ◽  
Vol 17 (9) ◽  
pp. e1009422
Author(s):  
M. Shahriar Karim ◽  
Aasakiran Madamanchi ◽  
James A. Dutko ◽  
Mary C. Mullins ◽  
David M. Umulis
Keyword(s):  
Distinct Type ◽  
Cell Types ◽  
Bmp Signaling ◽  
Biophysical Model ◽  
Transmembrane Receptors ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Wide Range ◽  
Multiple Cell ◽  
Organismal Development

Numerous stages of organismal development rely on the cellular interpretation of gradients of secreted morphogens including members of the Bone Morphogenetic Protein (BMP) family through transmembrane receptors. Early gradients of BMPs drive dorsal/ventral patterning throughout the animal kingdom in both vertebrates and invertebrates. Growing evidence in Drosophila, zebrafish, murine and other systems suggests that BMP ligand heterodimers are the primary BMP signaling ligand, even in systems in which mixtures of BMP homodimers and heterodimers are present. Signaling by heterodimers occurs through a hetero-tetrameric receptor complex comprising of two distinct type one BMP receptors and two type II receptors. To understand the system dynamics and determine whether kinetic assembly of heterodimer-heterotetramer BMP complexes is favored, as compared to other plausible BMP ligand-receptor configurations, we developed a kinetic model for BMP tetramer formation based on current measurements for binding rates and affinities. We find that contrary to a common hypothesis, heterodimer-heterotetramer formation is not kinetically favored over the formation of homodimer-tetramer complexes under physiological conditions of receptor and ligand concentrations and therefore other mechanisms, potentially including differential kinase activities of the formed heterotetramer complexes, must be the cause of heterodimer-heterotetramer signaling primacy. Further, although BMP complex assembly favors homodimer and homomeric complex formation over a wide range of parameters, ignoring these signals and instead relying on the heterodimer improves the range of morphogen interpretation in a broad set of conditions, suggesting a performance advantage for heterodimer signaling in patterning multiple cell types in a gradient.

scholarly journals The context-dependent, combinatorial logic of BMP signaling

2020 ◽  
Author(s):  
Heidi Klumpe ◽  
Matthew A. Langley ◽  
James M. Linton ◽  
Christina J. Su ◽  
Yaron E. Antebi ◽  
...  
Keyword(s):  
Communication Systems ◽  
Cell Communication ◽  
Bmp Signaling ◽  
Receptor Expression ◽  
Signaling Systems ◽  
Morphogenetic Protein ◽  
Pathway Activation ◽  
Ligand Interactions ◽  
Context Dependent ◽  
Combinatorial Interactions

SummaryCell-cell communication systems typically comprise families of ligand and receptor variants that function together in combinations. Pathway activation depends in a complex way on which ligands are present and what receptors are expressed by the signal-receiving cell. To understand the combinatorial logic of such a system, we systematically measured pairwise Bone Morphogenetic Protein (BMP) ligand interactions in cells with varying receptor expression. Ligands could be classified into equivalence groups based on their profile of positive and negative synergies with other ligands. These groups varied with receptor expression, explaining how ligands can functionally replace each other in one context but not another. Context-dependent combinatorial interactions could be explained by a biochemical model based on competitive formation of alternative signaling complexes with distinct activities. Together, these results provide insights into the roles of BMP combinations in developmental and therapeutic contexts and establish a framework for analyzing other combinatorial, context-dependent signaling systems.

scholarly journals Notch Signaling in Development, Tissue Homeostasis, and Disease

2017 ◽  
Vol 97 (4) ◽  
pp. 1235-1294 ◽  
Author(s):  
Chris Siebel ◽  
Urban Lendahl
Keyword(s):  
Notch Signaling ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Tissue Homeostasis ◽  
Cell Fates ◽  
Signaling Mechanism ◽  
Transmembrane Receptors ◽  
Notch Gene ◽  
Broad Variety

Notch signaling is an evolutionarily highly conserved signaling mechanism, but in contrast to signaling pathways such as Wnt, Sonic Hedgehog, and BMP/TGF-β, Notch signaling occurs via cell-cell communication, where transmembrane ligands on one cell activate transmembrane receptors on a juxtaposed cell. Originally discovered through mutations in Drosophila more than 100 yr ago, and with the first Notch gene cloned more than 30 yr ago, we are still gaining new insights into the broad effects of Notch signaling in organisms across the metazoan spectrum and its requirement for normal development of most organs in the body. In this review, we provide an overview of the Notch signaling mechanism at the molecular level and discuss how the pathway, which is architecturally quite simple, is able to engage in the control of cell fates in a broad variety of cell types. We discuss the current understanding of how Notch signaling can become derailed, either by direct mutations or by aberrant regulation, and the expanding spectrum of diseases and cancers that is a consequence of Notch dysregulation. Finally, we explore the emerging field of Notch in the control of tissue homeostasis, with examples from skin, liver, lung, intestine, and the vasculature.

scholarly journals Cytonemes in Tumorigenesis

2019 ◽  
Author(s):  
Marta Portela
Keyword(s):  
Cancer Progression ◽  
Tumour Progression ◽  
Cell Signalling ◽  
Cell Communication ◽  
Cell Types ◽  
Wing Disc ◽  
Genetic Ablation ◽  
The Past ◽  
Tumoral Cell ◽  
To Receive

Increasing evidence during the past two decades shows that cells interconnect and communicate through cytonemes. These cytoskeleton-driven extensions of specialized membrane territories have emerged as a novel alternative for cell to cell communication that are involved in development, physiology, and disease. Several recent studies have shown that signalling pathways mediated by cytonemes during development, are essential for certain tumoral cell types progression. In Drosophila wing disc EGFR and RET tumour models, cytoneme formation is required to receive signals from the neighbouring cells. Genetic ablation of cytonemes prevents tumour progression, restores apico-basal polarity, and improves survival. Furthermore, cytonemes in the Drosophila glial cells are essential for glioblastoma progression as they alter Wg/Fz1 signalling between glia and neurons. Research on cytoneme formation, maintenance, and cell signalling mechanisms will help to better understand not only physiological developmental processes and tissue homeostasis but also cancer progression.

Xenopus mothers against decapentaplegic is an embryonic ventralizing agent that acts downstream of the BMP-2/4 receptor

Development ◽  
1996 ◽  
Vol 122 (8) ◽  
pp. 2359-2366 ◽  
Author(s):  
G.H. Thomsen
Keyword(s):  
Signal Transduction ◽  
Signal Transduction Pathway ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Tgf Beta ◽  
Cell Fates ◽  
Axial Patterning ◽  
Morphogenetic Protein ◽  
Receptor Signal ◽  
Vertebrate Embryos

Dorsal-ventral patterning in vertebrate embryos is regulated by members of the TGF-beta family of growth and differentiation factors. In Xenopus the activins and Vg1 are potent dorsal mesoderm inducers while members of the bone morphogenetic protein (BMP) subclass pattern ventral mesoderm and regulate ectodermal cell fates. Receptors for ligands in the TGF-beta superfamily are serine-threonine kinases, but little is known about the components of the signal transduction pathway leading away from these receptors. In Drosophila the decapentaplegic protein (dpp), a homolog of vertebrate BMP-2 and BMP-4, functions in dorsal-ventral axial patterning, and a genetic screen for components involved in signaling by dpp has identified a gene named mothers against decapentaplegic (Mad). Mad encodes a unique, predicted cytoplasmic, protein containing no readily identified functional motifs. This report demonstrates that a gene closely related to Drosophila Mad exists in Xenopus (called XMad) and it exhibits activities consistent with a role in BMP signaling. XMad protein induces ventral mesoderm when overexpressed in isolated animal caps and it ventralizes embryos. Furthermore, XMad rescues phenotypes generated by a signaling-defective, dominant-negative, BMP-2/4 receptor. These results furnish evidence that XMad protein participates in vertebrate embryonic dorsal-ventral patterning by functioning in BMP-2/4 receptor signal transduction.

scholarly journals Activin B Induces Noncanonical SMAD1/5/8 Signaling via BMP Type I Receptors in Hepatocytes: Evidence for a Role in Hepcidin Induction by Inflammation in Male Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (3) ◽  
pp. 1146-1162 ◽  
Author(s):  
Susanna Canali ◽  
Amanda B. Core ◽  
Kimberly B. Zumbrennen-Bullough ◽  
Maria Merkulova ◽  
Chia-Yu Wang ◽  
...  
Keyword(s):  
Cell Types ◽  
Similar Degree ◽  
Type I ◽  
Activin Receptor ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Low Concentrations ◽  
Receptor Like Kinase ◽  
Anemia Of Inflammation

Abstract Induction of the iron regulatory hormone hepcidin contributes to the anemia of inflammation. Bone morphogenetic protein 6 (BMP6) signaling is a central regulator of hepcidin expression in the liver. Recently, the TGF-β/BMP superfamily member activin B was implicated in hepcidin induction by inflammation via noncanonical SMAD1/5/8 signaling, but its mechanism of action and functional significance in vivo remain uncertain. Here, we show that low concentrations of activin B, but not activin A, stimulate prolonged SMAD1/5/8 signaling and hepcidin expression in liver cells to a similar degree as canonical SMAD2/3 signaling, and with similar or modestly reduced potency compared with BMP6. Activin B stimulates hepcidin via classical activin type II receptors ACVR2A and ACVR2B, noncanonical BMP type I receptors activin receptor-like kinase 2 and activin receptor-like kinase 3, and SMAD5. The coreceptor hemojuvelin binds to activin B and facilitates activin B-SMAD1/5/8 signaling. Activin B-SMAD1/5/8 signaling has some selectivity for hepatocyte-derived cells and is not enabled by hemojuvelin in other cell types. Liver activin B mRNA expression is up-regulated in multiple mouse models of inflammation associated with increased hepcidin and hypoferremia, including lipopolysaccharide, turpentine, and heat-killed Brucella abortus models. Finally, the activin inhibitor follistatin-315 blunts hepcidin induction by lipopolysaccharide or B. abortus in mice. Our data elucidate a novel mechanism for noncanonical SMAD activation and support a likely functional role for activin B in hepcidin stimulation during inflammation in vivo.

scholarly journals BMP signaling inhibition in Drosophila secondary cells remodels the seminal proteome and self and rival ejaculate functions

2019 ◽  
Vol 116 (49) ◽  
pp. 24719-24728 ◽  
Author(s):  
Ben R. Hopkins ◽  
Irem Sepil ◽  
Sarah Bonham ◽  
Thomas Miller ◽  
Philip D. Charles ◽  
...  
Keyword(s):  
Seminal Fluid ◽  
Cell Types ◽  
Bmp Signaling ◽  
Secretory Cells ◽  
Normal Female ◽  
Seminal Fluid Proteins ◽  
Accessory Glands ◽  
Offspring Production ◽  
Morphogenetic Protein ◽  
And Function

Seminal fluid proteins (SFPs) exert potent effects on male and female fitness. Rapidly evolving and molecularly diverse, they derive from multiple male secretory cells and tissues. In Drosophila melanogaster, most SFPs are produced in the accessory glands, which are composed of ∼1,000 fertility-enhancing “main cells” and ∼40 more functionally cryptic “secondary cells.” Inhibition of bone morphogenetic protein (BMP) signaling in secondary cells suppresses secretion, leading to a unique uncoupling of normal female postmating responses to the ejaculate: refractoriness stimulation is impaired, but offspring production is not. Secondary-cell secretions might therefore make highly specific contributions to the seminal proteome and ejaculate function; alternatively, they might regulate more global—but hitherto undiscovered—SFP functions and proteome composition. Here, we present data that support the latter model. We show that in addition to previously reported phenotypes, secondary-cell-specific BMP signaling inhibition compromises sperm storage and increases female sperm use efficiency. It also impacts second male sperm, tending to slow entry into storage and delay ejection. First male paternity is enhanced, which suggests a constraint on ejaculate evolution whereby high female refractoriness and sperm competitiveness are mutually exclusive. Using quantitative proteomics, we reveal changes to the seminal proteome that surprisingly encompass alterations to main-cell–derived proteins, indicating important cross-talk between classes of SFP-secreting cells. Our results demonstrate that ejaculate composition and function emerge from the integrated action of multiple secretory cell types, suggesting that modification to the cellular make-up of seminal-fluid-producing tissues is an important factor in ejaculate evolution.

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