scholarly journals TGF-β signaling is essential for joint morphogenesis

2007 ◽  
Vol 177 (6) ◽  
pp. 1105-1117 ◽  
Author(s):  
Anna Spagnoli ◽  
Lynda O'Rear ◽  
Ronald L. Chandler ◽  
Froilan Granero-Molto ◽  
Douglas P. Mortlock ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Fluorescent Protein ◽  
Receptor Gene ◽  
Artificial Chromosome ◽  
Transforming Growth Factor Β ◽  
Gene Expressions ◽  
Β Receptor ◽  
Green Fluorescent

Despite its clinical significance, joint morphogenesis is still an obscure process. In this study, we determine the role of transforming growth factor β (TGF-β) signaling in mice lacking the TGF-β type II receptor gene (Tgfbr2) in their limbs (Tgfbr2PRX-1KO). In Tgfbr2PRX-1KO mice, the loss of TGF-β responsiveness resulted in the absence of interphalangeal joints. The Tgfbr2Prx1KO joint phenotype is similar to that in patients with symphalangism (SYM1-OMIM185800). By generating a Tgfbr2–green fluorescent protein–β–GEO–bacterial artificial chromosome β-galactosidase reporter transgenic mouse and by in situ hybridization and immunofluorescence, we determined that Tgfbr2 is highly and specifically expressed in developing joints. We demonstrated that in Tgfbr2PRX-1KO mice, the failure of joint interzone development resulted from an aberrant persistence of differentiated chondrocytes and failure of Jagged-1 expression. We found that TGF-β receptor II signaling regulates Noggin, Wnt9a, and growth and differentiation factor-5 joint morphogenic gene expressions. In Tgfbr2PRX-1KO growth plates adjacent to interphalangeal joints, Indian hedgehog expression is increased, whereas Collagen 10 expression decreased. We propose a model for joint development in which TGF-β signaling represents a means of entry to initiate the process.

Fibroblasts positive for meflin have anti-fibrotic property in pulmonary fibrosis

2021 ◽  
pp. 2003397
Author(s):  
Yoshio Nakahara ◽  
Naozumi Hashimoto ◽  
Koji Sakamoto ◽  
Atsushi Enomoto ◽  
Taylor S. Adams ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Single Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Normal Lung ◽  
Potential Marker ◽  
Rna Hybridisation ◽  
Secretory Phenotype

The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine of the pathogenesis of IPF, identification of functional fibroblasts is warranted. This study was aimed to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis. We characterised meflin-positive cells in a single cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. scRNA-seq combined with in situ RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic property to prevent pulmonary fibrosis. Although transforming growth factor-β-induced fibrogenesis and cell senescence with senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution. These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.

scholarly journals Alteration in transforming growth factor-β receptor expression in gallbladder disease: implications of chronic cholelithiasis and chronic Salmonella typhi infection

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Yogesh D. Walawalkar ◽  
Yatindra Vaidya ◽  
Vijayashree Nayak
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Receptor Gene ◽  
Gallbladder Disease ◽  
Fold Increase ◽  
Transforming Growth Factor Β ◽  
Salmonella Typhi ◽  
Receptor Expression ◽  
Β Receptor

Gallbladder cancer prevalence is ever increasing with <em>Salmonella typhi</em> chronic infection being one of the predisposing factors. Altered ratios or expression of transforming growth factor-β (TGF-β) receptors and changes in its function are associated with loss in anti-proliferative effects of TGF-β and cancer progression. Using reverse transcriptase polymerase chain reaction we monitor any changes in TGF-β receptor gene expression. We simultaneously screen for <em>S. typhi</em> within the samples. From 73 patients undergoing cholecystectomy 39-50% had significant expression (P&lt;0.05) of TGF-β receptor (TβR)- I and TβR-II during chronic cholelithiasis as compared to the remaining 19-23% with acute chronic cholelithiasis. There was no significant increase in TβR-III receptor expression. Patient’s positive for <em>S. typhi</em> (7/73) did not show any significant changes in expression of these receptors, thus indicating no direct relation in regulating the host TGFβ-signaling pathway. Further analysis on expression of downstream Smad components revealed that patients with up-regulated TGFβ receptor expression show &gt;2-fold increase in the RSmads and Co-Smads with a &gt;2-fold decrease in I-Smads. Thus gain of TβR-I and II expression in epithelial cells of the gallbladder was associated with chronic inflammatory stages of the gallbladder disease.

scholarly journals Chronic NOS inhibition actuates endothelial-mesenchymal transformation

2007 ◽  
Vol 292 (1) ◽  
pp. H285-H294 ◽  
Author(s):  
Edmond O’Riordan ◽  
Natalia Mendelev ◽  
Susann Patschan ◽  
Daniel Patschan ◽  
Jonathan Eskander ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Asymmetric Dimethylarginine ◽  
Transforming Growth Factor ◽  
Fluorescent Protein ◽  
Transforming Growth Factor Β ◽  
Tissue Growth ◽  
Collagen Xviii ◽  
Green Fluorescent

Chronic kidney diseases are accompanied by the accumulation of substances like asymmetric dimethylarginine, phenylacetic acid, homocysteine, and advanced glycation end products, known to either inhibit endothelial nitric oxide synthase (eNOS) or uncouple it, consequently limiting the amount of available nitric oxide (NO). Reduced bioavailability of NO induces endothelial dysfunction. An early loss of peritubular capillaries in tubulointerstitial fibrotic areas and injury to endothelial cells have been linked to progressive renal disease. Screening endothelial genes in cells treated with NOS inhibitors showed upregulation of collagen XVIII, a precursor of a potent antiangiogenic substance, endostatin. This finding was confirmed at the level of mRNA and protein expression. Tie-2 promoter-driven green fluorescent protein mice treated with nonhypertensinogenic doses of a NOS inhibitor exhibited upregulation of collagen XVIII/endostatin and rarefaction of capillary profiles. This was accompanied by the increased expression of transforming growth factor-β and connective tissue growth factor in the kidney. Occasional endothelial cells expressed both the marker of endothelial lineage (green fluorescent protein) and mesenchymal marker (α-smooth muscle actin or calponin). In vitro studies of endothelial cells treated with asymmetric dimethylarginine showed decreased expression of eNOS and Flk-1 and enhanced expression of calponin and fibronectin, additional markers of smooth muscle and mesenchymal cells. These cells overexpressed transforming growth factor-β and connective tissue growth factor, as well as endostatin. In conclusion, data presented here 1) ascribe to NO deficiency in endothelial cells the function of a profibrotic stimulus associated with the expression of an antiangiogenic fragment of collagen XVIII (endostatin) and 2) provide evidence of endothelial-mesenchymal transdifferentiation in the course of inhibition of NOS by a pathophysiologically important antagonist, asymmetric dimethylarginine. Both mechanisms may account for microvascular rarefaction.

Microsatellite instability and mutated type II transforming growth factor-β receptor gene in gliomas

1997 ◽  
Vol 112 (2) ◽  
pp. 251-256 ◽  
Author(s):  
Shuichi Izumoto ◽  
Norio Arita ◽  
Takanori Ohnishi ◽  
Shoju Hiraga ◽  
Takuyu Taki ◽  
...  
Keyword(s):  
Growth Factor ◽  
Microsatellite Instability ◽  
Transforming Growth Factor ◽  
Receptor Gene ◽  
Transforming Growth Factor Β ◽  
Type Ii ◽  
Β Receptor

Gfi-1B controls human erythroid and megakaryocytic differentiation by regulating TGF-β signaling at the bipotent erythro-megakaryocytic progenitor stage

Blood ◽  
2010 ◽  
Vol 115 (14) ◽  
pp. 2784-2795 ◽  
Author(s):  
Voahangy Randrianarison-Huetz ◽  
Benoit Laurent ◽  
Valérie Bardet ◽  
Gerard C. Blobe ◽  
François Huetz ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Receptor Gene ◽  
Erythroid Differentiation ◽  
Transforming Growth Factor Β ◽  
Type Iii ◽  
Smad2 Phosphorylation ◽  
Proliferation And Differentiation ◽  
Direct Target ◽  
Β Receptor

Abstract Growth factor independence-1B (Gfi-1B) is a transcriptional repressor essential for erythropoiesis and megakaryopoiesis. Targeted gene disruption of GFI1B in mice leads to embryonic lethality resulting from failure to produce definitive erythrocytes, hindering the study of Gfi-1B function in adult hematopoiesis. We here show that, in humans, Gfi-1B controls the development of erythrocytes and megakaryocytes by regulating the proliferation and differentiation of bipotent erythro-megakaryocytic progenitors. We further identify in this cell population the type III transforming growth factor-β receptor gene, TGFBR3, as a direct target of Gfi-1B. Knockdown of Gfi-1B results in altered transforming growth factor-β (TGF-β) signaling as shown by the increase in Smad2 phosphorylation and its inability to associate to the transcription intermediary factor 1-γ (TIF1-γ). Because the Smad2/TIF1-γ complex is known to specifically regulate erythroid differentiation, we propose that, by repressing TGF-β type III receptor (TβRΙII) expression, Gfi-1B favors the Smad2/TIF1-γ interaction downstream of TGF-β signaling, allowing immature progenitors to differentiate toward the erythroid lineage.

scholarly journals Kinetic Analysis of Smad Nucleocytoplasmic Shuttling Reveals a Mechanism for Transforming Growth Factor β-Dependent Nuclear Accumulation of Smads

2005 ◽  
Vol 25 (22) ◽  
pp. 9845-9858 ◽  
Author(s):  
Bernhard Schmierer ◽  
Caroline S. Hill
Keyword(s):  
Green Fluorescent Protein ◽  
Growth Factor ◽  
Nuclear Export ◽  
Transforming Growth Factor ◽  
Fluorescent Protein ◽  
Transforming Growth Factor Β ◽  
Nuclear Accumulation ◽  
Nucleocytoplasmic Shuttling ◽  
Green Fluorescent

ABSTRACT Upon transforming growth factor β (TGF-β) stimulation, Smads accumulate in the nucleus, where they regulate gene expression. Using fluorescence perturbation experiments on Smad2 and Smad4 fused to either enhanced green fluorescent protein or photoactivatable green fluorescent protein, we have studied the kinetics of Smad nucleocytoplasmic shuttling in a quantitative manner in vivo. We have obtained rate constants for import and export of Smad2 and show that the cytoplasmic localization of Smad2 in uninduced cells reflects its nuclear export being more rapid than import. We find that TGF-β-induced nuclear accumulation of Smad2 is caused by a pronounced drop in the export rate of Smad2 from the nucleus, which is associated with a strong decrease in nuclear mobility of Smad2 and Smad4. TGF-β-induced nuclear accumulation involves neither a release from cytoplasmic retention nor an increase in Smad2 import rate. Hence, TGF-β-dependent nuclear accumulation of Smad2 is caused exclusively by selective nuclear trapping of phosphorylated, complexed Smad2. The proposed mechanism reconciles signal-dependent nuclear accumulation of Smad2 with its continuous nucleocytoplasmic cycling properties.

scholarly journals Nuclear Function of Smad7 Promotes Myogenesis

2009 ◽  
Vol 30 (3) ◽  
pp. 722-735 ◽  
Author(s):  
Tetsuaki Miyake ◽  
Nezeka S. Alli ◽  
John C. McDermott
Keyword(s):  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Gene Activation ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Independent Function ◽  
Nuclear Function ◽  
Localization Signal ◽  
Β Receptor

ABSTRACT In the “canonical” view of transforming growth factor β (TGF-β) signaling, Smad7 plays an inhibitory role. While Smad7 represses Smad3 activation by TGF-β, it does not reverse the inhibitory effect of TGF-β on myogenesis, suggesting a different function in myogenic cells. We previously reported a promyogenic role of Smad7 mediated by an interaction with MyoD. Based on this association, we hypothesized a possible nuclear function of Smad7 independent of its role at the level of the receptor. We therefore engineered a chimera of Smad7 with a nuclear localization signal (NLS), which serves to prevent and therefore bypass binding to the TGF-β receptor while concomitantly constitutively localizing Smad7 to the nucleus. This Smad7-NLS did not repress Smad3 activation by TGF-β but did retain its ability to enhance myogenic gene activation and phenotypic myogenesis, indicating that the nuclear, receptor-independent function of Smad7 is sufficient to promote myogenesis. Furthermore, Smad7 physically interacts with MyoD and antagonizes the repressive effects of active MEK on MyoD. Reporter and myogenic conversion assays indicate a pivotal regulation of MyoD transcriptional properties by the balance between Smad7 and active MEK. Thus, Smad7 has a nuclear coactivator function that is independent of TGF-β signaling and necessary to promote myogenic differentiation.

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