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 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 Injury-induced BMP signaling negatively regulates Drosophila midgut homeostasis

2013 ◽  
Vol 201 (6) ◽  
pp. 945-961 ◽  
Author(s):  
Zheng Guo ◽  
Ian Driver ◽  
Benjamin Ohlstein
Keyword(s):  
Stem Cell ◽  
Signaling Pathway ◽  
Cell Number ◽  
Bmp Signaling ◽  
Polyposis Syndrome ◽  
Posterior Midgut ◽  
Morphogenetic Protein ◽  
Pathway Activation ◽  
Copper Cell ◽  
Insight Into

Although much is known about injury-induced signals that increase rates of Drosophila melanogaster midgut intestinal stem cell (ISC) proliferation, it is largely unknown how ISC activity returns to quiescence after injury. In this paper, we show that the bone morphogenetic protein (BMP) signaling pathway has dual functions during midgut homeostasis. Constitutive BMP signaling pathway activation in the middle midgut mediated regional specification by promoting copper cell differentiation. In the anterior and posterior midgut, injury-induced BMP signaling acted autonomously in ISCs to limit proliferation and stem cell number after injury. Loss of BMP signaling pathway members in the midgut epithelium or loss of the BMP signaling ligand decapentaplegic from visceral muscle resulted in phenotypes similar to those described for juvenile polyposis syndrome, a human intestinal tumor caused by mutations in BMP signaling pathway components. Our data establish a new link between injury and hyperplasia and may provide insight into how BMP signaling mutations drive formation of human intestinal cancers.

scholarly journals Cross Talk between Insulin and Bone Morphogenetic Protein Signaling Systems in Brown Adipogenesis

2010 ◽  
Vol 30 (17) ◽  
pp. 4224-4233 ◽  
Author(s):  
Hongbin Zhang ◽  
Tim J. Schulz ◽  
Daniel O. Espinoza ◽  
Tian Lian Huang ◽  
Brice Emanuelli ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Cross Talk ◽  
Suppressive Effect ◽  
Bmp Signaling ◽  
Protein Signaling ◽  
Signaling Systems ◽  
Morphogenetic Protein ◽  
High Level ◽  
Signaling Components ◽  
Brown Adipogenesis

ABSTRACT Both insulin and bone morphogenetic protein (BMP) signaling systems are important for adipocyte differentiation. Analysis of gene expression in BMP7-treated fibroblasts revealed a coordinated change in insulin signaling components by BMP7. To further investigate the cross talk between insulin and BMP signaling systems in brown adipogenesis, we examined the effect of BMP7 in insulin receptor substrate 1 (IRS-1)-deficient brown preadipocytes, which exhibit a severe defect in differentiation. Treatment of these cells with BMP7 for 3 days prior to adipogenic induction restored differentiation and expression of brown adipogenic markers. The high level of adipogenic inhibitor preadipocyte factor 1 (Pref-1) in IRS-1-null cells was markedly reduced by 3 days of BMP7 treatment, and analysis of the 1.3-kb pref-1 promoter revealed 9 putative Smad binding elements (SBEs), suggesting that BMP7 could directly suppress Pref-1 expression, thereby allowing the initiation of the adipogenic program. Using a series of sequential deletion mutants of the pref-1 promoter linked to the luciferase gene and chromatin immunoprecipitation, we demonstrate that the promoter-proximal SBE (−192/−184) was critical in mediating BMP7's suppressive effect on pref-1 transcription. Together, these data suggest cross talk between the insulin and BMP signaling systems by which BMP7 can rescue brown adipogenesis in cells with insulin resistance.

scholarly journals Neuron-Radial Glial Cell Communication via BMP/Id1 Signaling Is Key to Long-Term Maintenance of the Regenerative Capacity of the Adult Zebrafish Telencephalon

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2794
Author(s):  
Gaoqun Zhang ◽  
Luisa Lübke ◽  
Fushun Chen ◽  
Tanja Beil ◽  
Masanari Takamiya ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Notch Pathway ◽  
Cell Communication ◽  
Bmp Signaling ◽  
Adult Brain ◽  
Adult Zebrafish ◽  
Regenerative Capacity ◽  
Signaling Systems ◽  
Genetic Ablation ◽  
Signaling Axis

The central nervous system of adult zebrafish displays an extraordinary neurogenic and regenerative capacity. In the zebrafish adult brain, this regenerative capacity relies on neural stem cells (NSCs) and the careful management of the NSC pool. However, the mechanisms controlling NSC pool maintenance are not yet fully understood. Recently, Bone Morphogenetic Proteins (BMPs) and their downstream effector Id1 (Inhibitor of differentiation 1) were suggested to act as key players in NSC maintenance under constitutive and regenerative conditions. Here, we further investigated the role of BMP/Id1 signaling in these processes, using different genetic and pharmacological approaches. Our data show that BMPs are mainly expressed by neurons in the adult telencephalon, while id1 is expressed in NSCs, suggesting a neuron-NSC communication via the BMP/Id1 signaling axis. Furthermore, manipulation of BMP signaling by conditionally inducing or repressing BMP signaling via heat-shock, lead to an increase or a decrease of id1 expression in the NSCs, respectively. Induction of id1 was followed by an increase in the number of quiescent NSCs, while knocking down id1 expression caused an increase in NSC proliferation. In agreement, genetic ablation of id1 function lead to increased proliferation of NSCs, followed by depletion of the stem cell pool with concomitant failure to heal injuries in repeatedly injured mutant telencephala. Moreover, pharmacological inhibition of BMP and Notch signaling suggests that the two signaling systems cooperate and converge onto the transcriptional regulator her4.1. Interestingly, brain injury lead to a depletion of NSCs in animals lacking BMP/Id1 signaling despite an intact Notch pathway. Taken together, our data demonstrate how neurons feedback on NSC proliferation and that BMP1/Id1 signaling acts as a safeguard of the NSC pool under regenerative conditions.

The Bone Morphogenetic Protein (BMP)-4 Is Involved in the Regulation of Human Megakaryocytic Differentiation during Thrombopoietin Signaling.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1339-1339
Author(s):  
Franck E Nicolini ◽  
Sandrine Jeanpierre ◽  
Bastien Kaniewski ◽  
Charles Dumontet ◽  
Ruth Rimokh ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Activin A ◽  
Bmp Signaling ◽  
Receptor Expression ◽  
Autocrine Loop ◽  
Megakaryocytic Differentiation ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
The Impact

Abstract It has been shown in the past that Activin A, BMP-2 and BMP-4, three members of the TGF-β family, are involved in the regulation of hematopoiesis and particularly erythropoiesis, in humans. In this study, we explored the role of these molecules in human megakaryopoiesis using an in vitro serum-free assay initiated with purified normal CD34+ human bone marrow (BM) cells (from allogeneic BM donors), that allows the analysis of the impact of such molecules on all stages of megakaryocytic differentiation. We could demonstrate for the first time, that in the absence of thrombopoietin (TPO), BMP-4 is able to induce CD34+ progenitor commitment and differentiation into megakaryocytes throughout all stages through means of cytology, flow cytometry, CFU and LTC-IC and ploidy assays, as well as in vitro platelet production. We analyzed as well the expression of megakaryocytic specific factors such as FOG-2, Fli-1 and PF4 by RQ-PCR, and PF4, BMP-4 secretion in culture supernatants. While we have previously shown that Activin A and BMP-2 are involved in the erythropoietic commitment even in the absence of erythropoietin, we were not able to demonstrate any effect of these molecules on megakaryopoietic commitment and differentiation. Using signaling pathways specific inhibitors such as AG490 (JAK-2 pathway inhibitor), PD98059 (ERK pathway inhibitor), LY294002 (PI3-K inhibitor) and Rapamycin (mTOR pathway inhibitor), we could show that BMP-4, as TPO, exerts its effects on human megakaryopoiesis involving specifically the JAK/STAT and mTOR signaling pathways. In addition, the specific inhibition of the BMP signaling pathway with blocking antibodies (CD34+ BM cells cultured in the presence of anti-TPO-R and mouse anti-BMP-4 Antibody), natural soluble inhibitors [such as FLRG (Follistatin related gene) protein or Follistatin], or soluble BMP-receptors (sBMPR-Ia, sBMPR-Ib) has revealed that TPO uses the BMP-4 pathway to induce the megakaryopoietic commitment of human BM CD34+ progenitors. Finally, we could demonstrate that TPO up-regulates a BMP-4 autocrine loop in megakaryocytic progenitors, by inducing their own production of BMP-4 associated to an up-regulation of BMP-receptor expression. In conclusion, this study illustrates that BMP-4 represents an important actor in the regulation of human megakaryopoiesis.

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.

Plant peptide hormone signalling

2015 ◽  
Vol 58 ◽  
pp. 115-131 ◽  
Author(s):  
Ayane Motomitsu ◽  
Shinichiro Sawa ◽  
Takashi Ishida
Keyword(s):  
Communication Systems ◽  
Cell Communication ◽  
Peptide Hormone ◽  
Peptide Hormones ◽  
Target Cells ◽  
Signalling Molecules ◽  
Receptor Complexes ◽  
Environmental Responses ◽  
Plant Life Cycle ◽  
Multicellular Organisms

The ligand–receptor-based cell-to-cell communication system is one of the most important molecular bases for the establishment of complex multicellular organisms. Plants have evolved highly complex intercellular communication systems. Historical studies have identified several molecules, designated phytohormones, that function in these processes. Recent advances in molecular biological analyses have identified phytohormone receptors and signalling mediators, and have led to the discovery of numerous peptide-based signalling molecules. Subsequent analyses have revealed the involvement in and contribution of these peptides to multiple aspects of the plant life cycle, including development and environmental responses, similar to the functions of canonical phytohormones. On the basis of this knowledge, the view that these peptide hormones are pivotal regulators in plants is becoming increasingly accepted. Peptide hormones are transcribed from the genome and translated into peptides. However, these peptides generally undergo further post-translational modifications to enable them to exert their function. Peptide hormones are expressed in and secreted from specific cells or tissues. Apoplastic peptides are perceived by specialized receptors that are located at the surface of target cells. Peptide hormone–receptor complexes activate intracellular signalling through downstream molecules, including kinases and transcription factors, which then trigger cellular events. In this chapter we provide a comprehensive summary of the biological functions of peptide hormones, focusing on how they mature and the ways in which they modulate plant functions.

scholarly journals Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling

2021 ◽  
Vol 7 (7) ◽  
pp. eabf1798
Author(s):  
A. Murashima-Suginami ◽  
H. Kiso ◽  
Y. Tokita ◽  
E. Mihara ◽  
Y. Nambu ◽  
...  
Keyword(s):  
Tooth Development ◽  
Bmp Signaling ◽  
Tooth Agenesis ◽  
Tooth Regeneration ◽  
Missing Teeth ◽  
Morphogenetic Protein ◽  
Genetic Abnormalities ◽  
Direct Binding ◽  
Tooth Germs ◽  
Lipoprotein Receptor Related Protein

Uterine sensitization–associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor–related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti–USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti–USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

scholarly journals GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone

2020 ◽  
Vol 117 (9) ◽  
pp. 4910-4920 ◽  
Author(s):  
Joonho Suh ◽  
Na-Kyung Kim ◽  
Seung-Hoon Lee ◽  
Je-Hyun Eom ◽  
Youngkyun Lee ◽  
...  
Keyword(s):  
Bone Mass ◽  
Muscle Mass ◽  
Transforming Growth Factor ◽  
Bone Fractures ◽  
Muscle Growth ◽  
Transforming Growth Factor Β ◽  
Biochemical Properties ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Perinatal Lethality

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor β (TGF-β) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality ofGdf11null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show thatGdf11null mice, despite significantly down-regulatingMstnexpression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed inMstnnull mice that display enhanced bone mass. Mechanistically,Mstndeletion up-regulatesGdf11expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlikeMstnnull mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

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