scholarly journals Bone Morphogenetic Protein Signaling Restricts Proximodistal Extension of the Ventral Fin Fold

2020 ◽  
Vol 8 ◽  
Author(s):  
Jun Ka ◽  
Jun-Dae Kim ◽  
Boryeong Pak ◽  
Orjin Han ◽  
Woosoung Choi ◽  
...  
Keyword(s):  
Cell Division ◽  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Bmp Signaling ◽  
Protein Signaling ◽  
Morphogenetic Protein ◽  
Distal Migration ◽  
Cellular Behaviors ◽  
And Shifts ◽  
Migration Of Cells

Unpaired fins, which are the most ancient form of locomotory appendages in chordates, had emerged at least 500 million years ago. While it has been suggested that unpaired fins and paired fins share structural similarities, cellular and molecular mechanisms that regulate the outgrowth of the former have not been fully elucidated yet. Using the ventral fin fold in zebrafish as a model, here, we investigate how the outgrowth of the unpaired fin is modulated. We show that Bone Morphogenetic Protein (BMP) signaling restricts extension of the ventral fin fold along the proximodistal axis by modulating diverse aspects of cellular behaviors. We find that lack of BMP signaling, either caused by genetic or chemical manipulation, prolongs the proliferative capacity of epithelial cells and substantially increases the number of cells within the ventral fin fold. In addition, inhibition of BMP signaling attenuates the innate propensity of cell division along the anteroposterior axis and shifts the orientation of cell division toward the proximodistal axis. Moreover, abrogating BMP signaling appears to induce excessive distal migration of cells within the ventral fin fold, and therefore precipitates extension along the proximodistal axis. Taken together, our data suggest that BMP signaling restricts the outgrowth of the ventral fin fold during zebrafish development.

scholarly journals Bone morphogenetic protein signaling in inflammation

2019 ◽  
Vol 244 (2) ◽  
pp. 147-156 ◽  
Author(s):  
David H Wu ◽  
Antonis K Hatzopoulos
Keyword(s):  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Therapeutic Interventions ◽  
Protein Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Morphogenetic Protein ◽  
Therapeutic Value ◽  
Organ Systems ◽  
Different Tissues

Bone morphogenetic protein signaling has long been established as a crucial pathway during embryonic development. In recent years, our knowledge of the function of bone morphogenetic protein signaling has expanded dramatically beyond solely its important role in development. Today, the pathway is known to have important homeostatic functions across multiple different tissues in the adult. Even more importantly, bone morphogenetic protein signaling is now known to function as a driver of diseases in the adult spanning different organ systems. In this review, we will explore the functions of bone morphogenetic protein signaling in diseases of inflammation. Through this exploration, we will highlight the value and challenges in targeting bone morphogenetic protein signaling for therapeutic interventions. Impact statement By compiling findings from recent studies, this review will garner novel insight on the dynamic and complex role of BMP signaling in diseases of inflammation, highlighting the specific roles played by both individual ligands and endogenous antagonists. Ultimately, this summary will help inform the high therapeutic value of targeting this pathway for modulating diseases of inflammation.

scholarly journals Netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ahmad Abdullah ◽  
Carl Herdenberg ◽  
Håkan Hedman
Keyword(s):  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Bmp Signaling ◽  
Cellular Systems ◽  
Axonal Guidance ◽  
Inhibitory Interaction ◽  
Inhibitory Function ◽  
Morphogenetic Protein ◽  
Cell Metastasis ◽  
Leucine Rich Repeats

AbstractNetrin-1 is a secreted protein that is well known for its involvement in axonal guidance during embryonic development and as an enhancer of cancer cell metastasis. Despite extensive efforts, the molecular mechanisms behind many of the physiological functions of netrin-1 have remained elusive. Here, we show that netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling in various cellular systems, including a mutually inhibitory interaction with the BMP-promoting function of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins. The BMP inhibitory function of netrin-1 in mouse embryonic fibroblasts was dependent on the netrin receptor neogenin, with the expression level regulated by both netrin-1 and LRIG proteins. Our results reveal a previously unrecognized function of netrin-1 that may help to explain several of the developmental, physiological, and cancer-promoting functions of netrins at the signal transduction level.

scholarly journals Paracrine Bone Morphogenetic Protein Signaling in Iron Homeostasis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-26-SCI-26
Author(s):  
Jodie L. Babitt
Keyword(s):  
Iron Deficiency ◽  
Bone Morphogenetic Protein ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Bmp Signaling ◽  
Free Oxygen Radicals ◽  
Iron Loading ◽  
Iron Availability ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Iron is an essential nutrient that is required not only for hemoglobin production in red blood cells, but also as a co-factor of many other proteins that perform fundamental cellular processes. However, excess iron can generate free oxygen radicals that can be toxic. Cells and organisms have therefore evolved mechanisms to tightly control iron levels. Systemic iron homeostasis is governed by the iron hormone hepcidin that binds and degrades the iron exporter ferroportin to limit iron absorption from dietary sources and iron release from iron-recycling macrophages and hepatocyte stores. The key source of hepcidin that controls systemic iron homeostasis is the liver. Hepcidin production by the liver is coordinated by several signals that communicate the body's iron needs. Increases in serum and tissue iron induce hepcidin production, whereas iron deficiency suppresses hepcidin production, as feedback mechanisms to maintain steady state iron levels. Inflammation induces hepcidin to limit iron availability to infectious organisms that also require iron to grow and proliferate. Increases in erythropoietic drive suppress hepcidin production to increase iron availability for red blood cell production. The bone morphogenetic protein (BMP) signaling pathway is the central signal transduction pathway that controls hepcidin production in the liver. Activation of BMP signaling by iron loading or suppression of BMP signaling by iron deficiency or erythropoietic drive are key mechanisms by which these signals control hepcidin transcription. Iron loading increases production of BMP6 and BMP2 ligands by liver endothelial cells. Endothelial-derived BMP6 and BMP2 have paracrine actions on BMP receptors and the co-receptor hemojuvelin on hepatocytes to phosphorylate SMAD transcription factors, which translocate to the nucleus to regulate hepcidin transcription. Erythropoietic drive increases the production of erythroferrone by erythrocyte precursors. Erythroferrone is secreted into the circulation where it binds BMP ligands to prevent their interaction with cell surface receptors, thereby inhibiting hepcidin transcription. This talk will focus on recent insights into the molecular mechanisms by whch paracrine BMP signaling in the liver coordinates hepcidin production to regulate systemic iron homeostasis. Disclosures Babitt: Ferrumax Pharmaceuticals, Inc: Equity Ownership, Patents & Royalties; Keryx BIopharmaceuticals, Inc (now part of Akebia Therapeutics): Consultancy; Disc Medicine: Consultancy.

scholarly journals Essential Roles of Epithelial Bone Morphogenetic Protein Signaling During Prostatic Development

Endocrinology ◽  
2014 ◽  
Vol 155 (7) ◽  
pp. 2534-2544 ◽  
Author(s):  
Akiko Omori ◽  
Shinichi Miyagawa ◽  
Yukiko Ogino ◽  
Masayo Harada ◽  
Kenichiro Ishii ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Regulatory Gene ◽  
Epithelial Differentiation ◽  
Bmp Signaling ◽  
Urogenital Sinus ◽  
Protein Signaling ◽  
Morphogenetic Protein ◽  
Key Factor ◽  
Male Sex ◽  
Luminal Cells

Prostate is a male sex-accessory organ. The prostatic epithelia consist primarily of basal and luminal cells that differentiate from embryonic urogenital sinus epithelia. Prostate tumors are believed to originate in the basal and luminal cells. However, factors that promote normal epithelial differentiation have not been well elucidated, particularly for bone morphogenetic protein (Bmp) signaling. This study shows that Bmp signaling prominently increases during prostatic differentiation in the luminal epithelia, which is monitored by the expression of phosphorylated Smad1/5/8. To elucidate the mechanism of epithelial differentiation and the function of Bmp signaling during prostatic development, conditional male mutant mouse analysis for the epithelial-specific Bmp receptor 1a (Bmpr1a) was performed. We demonstrate that Bmp signaling is indispensable for luminal cell maturation, which regulates basal cell proliferation. Expression of the prostatic epithelial regulatory gene Nkx3.1 was significantly reduced in the Bmpr1a mutants. These results indicate that Bmp signaling is a key factor for prostatic epithelial differentiation, possibly by controlling the prostatic regulatory gene Nkx3.1.

scholarly journals Bone morphogenetic protein signaling regulates Id1 mediated neural stem cell quiescence in the adult zebrafish brain via a phylogenetically conserved enhancer module

2019 ◽  
Author(s):  
Gaoqun Zhang ◽  
Marco Ferg ◽  
Luisa Lübke ◽  
Masanari Takamiya ◽  
Tanja Beil ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Transgenic Zebrafish ◽  
Deletion Mapping ◽  
Protein Signaling ◽  
Adult Zebrafish ◽  
Specific Expression ◽  
Radial Glial Cells ◽  
Morphogenetic Protein ◽  
Stem Cell Quiescence

AbstractIn the telencephalon of adult zebrafish, the inhibitor of DNA binding 1 (id1) gene is expressed in radial glial cells (RGCs), behaving as neural stem cells (NSCs), during constitutive and regenerative neurogenesis. Id1 controls the balance between resting and proliferating states of RGCs by promoting quiescence. Here, we identified a phylogenetically conserved cis-regulatory module (CRM) mediating the specific expression of id1 in RGCs. Systematic deletion mapping and mutation of conserved transcription factor binding sites in stable transgenic zebrafish lines reveal that this CRM operates via conserved smad1/5 and 4 binding motifs (SBMs) under both homeostatic and regenerative conditions. Transcriptome analysis of injured and uninjured telencephala as well as pharmacological inhibition experiments identify a crucial role of bone morphogenetic protein (BMP) signaling for the function of the CRM. Our data highlight that BMP signals control id1 expression and thus NSC proliferation during constitutive and induced neurogenesis.

scholarly journals Bone morphogenetic protein 2 inhibits growth differentiation factor 8-induced cell signaling via upregulation of gremlin2 expression in human granulosa-lutein cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaoyan Luo ◽  
Hsun-Ming Chang ◽  
Yuyin Yi ◽  
Yingpu Sun ◽  
Peter C. K. Leung
Keyword(s):  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Differentiation Factor ◽  
Morphogenetic Protein

Abstract Background Bone morphogenetic protein 2 (BMP2), growth differentiation factor 8 (GDF8) and their functional receptors are expressed in human ovarian follicles, and these two intrafollicular factors play essential roles in regulating follicle development and luteal function. As BMP antagonists, gremlin1 (GREM1) and gremlin2 (GREM2) suppress BMP signaling through blockage of ligand-receptor binding. However, whether BMP2 regulates the expression of GREM1 and GREM2 in follicular development remains to be determined. Methods In the present study, we investigated the effect of BMP2 on the expression of GREM1 and GREM2 and the underlying mechanisms in human granulosa-lutein (hGL) cells. An established immortalized human granulosa cell line (SVOG) and primary hGL cells were used as study models. The expression of GREM1 and GREM2 were examined following cell incubation with BMP2 at different concentrations and time courses. The TGF-β type I inhibitors (dorsomorphin, DMH-1 and SB431542) and small interfering RNAs targeting ALK2, ALK3, SMAD2/3, SMAD1/5/8 and SMAD4 were used to investigate the involvement of the SMAD-dependent pathway. Results Our results showed that BMP2 significantly increased the expression of GREM2 (but not GREM1) in a dose- and time-dependent manner. Using a dual inhibition approach combining kinase inhibitors and siRNA-mediated knockdown, we found that the BMP2-induced upregulation of GREM2 expression was mediated by the ALK2/3-SMAD1/5-SMAD4 signaling pathway. Moreover, we demonstrated that BMP2 pretreatment significantly attenuated the GDF8-induced phosphorylation of SMAD2 and SMAD3, and this suppressive effect was reversed by knocking down GREM2 expression. Conclusions Our findings provide new insight into the molecular mechanisms by which BMP2 modulates the cellular activity induced by GDF8 through the upregulated expression of their antagonist (GREM2).

scholarly journals Constitutively Active Akt Induces Ectodermal Defects and Impaired Bone Morphogenetic Protein Signaling

2008 ◽  
Vol 19 (1) ◽  
pp. 137-149 ◽  
Author(s):  
Carmen Segrelles ◽  
Marta Moral ◽  
Corina Lorz ◽  
Mirentxu Santos ◽  
Jerry Lu ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Basal Layer ◽  
Gene Profiling ◽  
Epithelial Tissue ◽  
Dependent Manner ◽  
Protein Signaling ◽  
Morphogenetic Protein ◽  
Constitutively Active

Aberrant activation of the Akt pathway has been implicated in several human pathologies including cancer. However, current knowledge on the involvement of Akt signaling in development is limited. Previous data have suggested that Akt-mediated signaling may be an essential mediator of epidermal homeostasis through cell autonomous and noncell autonomous mechanisms. Here we report the developmental consequences of deregulated Akt activity in the basal layer of stratified epithelia, mediated by the expression of a constitutively active Akt1 (myrAkt) in transgenic mice. Contrary to mice overexpressing wild-type Akt1 (Aktwt), these myrAkt mice display, in a dose-dependent manner, altered development of ectodermally derived organs such as hair, teeth, nails, and epidermal glands. To identify the possible molecular mechanisms underlying these alterations, gene profiling approaches were used. We demonstrate that constitutive Akt activity disturbs the bone morphogenetic protein-dependent signaling pathway. In addition, these mice also display alterations in adult epidermal stem cells. Collectively, we show that epithelial tissue development and homeostasis is dependent on proper regulation of Akt expression and activity.

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.

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