scholarly journals Activin βC and βE Genes Are Not Essential for Mouse Liver Growth, Differentiation, and Regeneration

2000 ◽  
Vol 20 (16) ◽  
pp. 6127-6137 ◽  
Author(s):  
Anthony L. Lau ◽  
T. Rajendra Kumar ◽  
Katsuhiko Nishimori ◽  
Jeffrey Bonadio ◽  
Martin M. Matzuk
Keyword(s):  
Embryonic Development ◽  
Transforming Growth Factor ◽  
Serum Proteins ◽  
Embryonic Stem ◽  
Transforming Growth Factor Β ◽  
Wild Type ◽  
Rnase Protection ◽  
Liver Growth ◽  
Adult Mice ◽  
The Individual

ABSTRACT The liver is an essential organ that produces several serum proteins, stores vital nutrients, and detoxifies many carcinogenic and xenobiotic compounds. Various growth factors positively regulate liver growth, but only a few negative regulators are known. Among the latter are the transforming growth factor β (TGF-β) superfamily members TGF-β1 and activin A. To study the function of novel activin family members, we have cloned and generated mice deficient in the activin βC and βE genes. Expression analyses demonstrated that these novel genes are liver specific in adult mice. Here, we show by RNase protection that activin βC transcripts are present in the liver beginning at embryonic day 11.5 (E11.5) whereas activin βE expression is detected starting from E17.5. Gene targeting in embryonic stem cells was used to generate mice with null mutations in either the individual activin βC and βE genes or both genes. In contrast to the structurally related activin βA and βB subunits, which are necessary for embryonic development and pituitary follicle-stimulating hormone homeostasis, mice deficient in activin βC and βE were viable, survived to adulthood, and demonstrated no reproductive abnormalities. Although activin βC and βE mRNAs are abundantly expressed in the liver of wild-type mice, the single and double mutants did not show any defects in liver development and function. Furthermore, in the homozygous mutant mice, liver regeneration after >70% partial hepatectomy was comparable to that in wild-type mice. Our results suggest that activin βC and βE are not essential for either embryonic development or liver function.

COX-2 is not required for the development of murine chronic pancreatitis

2011 ◽  
Vol 300 (6) ◽  
pp. G968-G975 ◽  
Author(s):  
Alberto Silva ◽  
Achim Weber ◽  
Martha Bain ◽  
Theresia Reding ◽  
Mathias Heikenwalder ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Collagen Deposition ◽  
Wild Type ◽  
Therapeutic Implications ◽  
Adult Mice ◽  
Cox 2 ◽  
Species Specific

Chronic pancreatitis is a severe inflammation of the pancreas associated with destruction of the parenchyma, fibrosis, and persistent abdominal pain. Cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandins, key mediators of the inflammatory response, are elevated in patients with chronic pancreatitis. Previous studies investigated COX-2 as a therapeutic target. These reports showed a reduced pathology in COX-2-deficient mice with a better outcome. Here we compared the role of COX-2 in acute and chronic pancreatic inflammation using the same COX-2−/− mouse model of cerulein-induced pancreatitis. In a setting of acute pancreatitis, juvenile COX-2−/− mice exhibited a reduced histopathological score compared with wild-type littermates; on the contrary, adult mice did not show any difference in the development of the disease. Similarly, in a setting of chronic pancreatitis induced over a period of 4 wk, adult mice of the two strains showed comparable histological score and collagen deposition. However, the abundance of mRNAs coding for profibrotic genes, such as collagen, α-smooth muscle actin, and transforming growth factor-β was consistently lower in COX-2−/− mice. In addition, comparable histological scores and collagen deposition were observed in wild-type mice treated with a COX-2 inhibitor. We conclude that, in contrast to what was observed in the rat pancreatitis models, COX-2 has a limited and age-dependent effect on inflammatory processes in the mouse pancreas. These results suggest that COX-2 modulates the inflammatory process during the development of pancreatitis in a species-specific manner. Thus the pathophysiological roles of COX-2 and its therapeutic implications in patients with pancreatitis should be reexamined.

scholarly journals TAK1 deficiency attenuates cisplatin-induced acute kidney injury

2020 ◽  
Vol 318 (1) ◽  
pp. F209-F215 ◽  
Author(s):  
Jun Zhou ◽  
Changlong An ◽  
Xiaogao Jin ◽  
Zhaoyong Hu ◽  
Robert L. Safirstein ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Proximal Tubule ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Kidney Injury ◽  
Transforming Growth Factor Β ◽  
Tubular Epithelial Cell ◽  
Tubular Damage ◽  
Wild Type ◽  
Deficient Mice

Cisplatin can cause acute kidney injury (AKI), but the molecular mechanisms are not well understood. The objective of the present study was to examine the role of transforming growth factor-β-activated kinase-1 (TAK1) in the pathogenesis of cisplatin-induced AKI. Wild-type mice and proximal tubule TAK1-deficient mice were treated with vehicle or cisplatin. Compared with wild-type control mice, proximal tubule TAK1-deficient mice had less severe kidney dysfunction, tubular damage, and apoptosis after cisplatin–induced AKI. Furthermore, conditional disruption of TAK1 in proximal tubular epithelial cells reduced caspase-3 activation, proinflammatory molecule expression, and JNK phosphorylation in the kidney in cisplatin-induced AKI. Taken together, cisplatin activates TAK1-JNK signaling pathway to promote tubular epithelial cell apoptosis and inflammation in cisplatin-induced AKI. Targeting TAK1 could be a novel therapeutic strategy against cisplatin-induced AKI.

208 EFFECT OF GDF8 AND SB-431542 ON PORCINE OOCYTE DURING IN VITRO MATURATION AND SUBSEQUENT EMBRYONIC DEVELOPMENT

2016 ◽  
Vol 28 (2) ◽  
pp. 235
Author(s):  
J. D. Yoon ◽  
E. Lee ◽  
S.-H. Hyun
Keyword(s):  
Treatment Group ◽  
Embryonic Development ◽  
Follicular Fluid ◽  
In Vitro Maturation ◽  
Transforming Growth Factor ◽  
Formation Rate ◽  
Transforming Growth Factor Β ◽  
Nuclear Maturation ◽  
Porcine Oocyte

Growth differentiation factor-8 (GDF8) is a member of the transforming growth factor-β that has been identified as a strong physiological regulator. SB-431542 (SB) is a specific inhibitor of transforming growth factor-β superfamily type I activin receptor-like kinase (ALK) receptors such as ALK4, ALK5, and ALK7. The purpose of this study is investigation of the effects of GDF8 and SB on porcine oocytes during in vitro maturation and subsequent embryonic development. We first performed ELISA to detect GDF8 concentrations in follicular fluid for each size of follicle; sizes were as follows: small (<3 mm), medium (>3 mm and <6 mm), and large (>6 mm) follicle. After detection of the GDF8 concentration in follicular fluid, we investigated the effect of GDF8 and SB treatment during in vitro maturation (IVM) on nuclear maturation, intracellular glutathione (GSH), and reactive oxygen species (ROS) levels, and embryonic development after IVF and parthenogenetic activation (PA). Data were analysed by ANOVA followed by Duncan using SPSS (Statistical Package for Social Science, IBM, New York, NY, USA) mean ± SEM. The ELISA result showed different concentrations of GDF8 for each grade of follicular fluid: small, 0.479 ng mL–1; medium, 0.668 ng mL–1; and large, 1.318 ng mL–1. During the IVM process, 1.318 ng mL–1 of GDF8 and 5 ng mL–1 of SB were added to the maturation medium as control, SB, SB+GDF8, and GDF8 treatment groups. After 44 h of IVM, GDF8 group (90.4%) showed a significantly higher nuclear maturation rate than control and SB+GDF8 groups (85.4 and 81.7%). The SB group (78.9%) showed significantly reduced nuclear maturation rate compared with control (P < 0.05). The GDF8 treatment group showed a significant decreased intracellular ROS and increased GSH levels compared with other groups (P < 0.05). The SB+GBF8 treatment group showed a significantly better cytoplasmic maturation than the SB treatment group. In the PA embryonic development analysis, the GDF8 treatment group showed a significantly higher blastocyst formation rate compared with other groups (47.9, 37.2, 46.4, and 58.7% respectively; P < 0.05). In the IVF embryonic development analysis, the GDF8 treatment groups showed significantly higher blastocyst formation rate compared with the SB group (28.2 and 42.2%, respectively; P < 0.05). In conclusion, treatment with GDF8 during porcine oocyte IVM improved the embryonic developmental competence via increased cytoplasmic maturation and led to better oocyte maturation from the ALK receptor inhibition by SB.

More than a cell biosensor: aryl hydrocarbon receptor at the intersection of physiology and inflammation

2020 ◽  
Vol 318 (6) ◽  
pp. C1078-C1082 ◽  
Author(s):  
Tiziana Guarnieri ◽  
Provvidenza Maria Abruzzo ◽  
Alessandra Bolotta
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Inflammatory Mediators ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Downstream Target ◽  
Aryl Hydrocarbon ◽  
Inflammatory State ◽  
A Cell ◽  
The Individual ◽  
Inflammatory Molecules

Aryl hydrocarbon receptor (AhR), a highly conserved intracellular transcription factor, is activated by a plethora of ligands of both exogenous and endogenous nature. Besides activating xenobiotic-metabolizing enzymes, it is involved in the differentiation and development of hematopoietic, hepatic, nervous and immune systems. More and more data describe its role in the regulation of immune responses and in the onset and progression of inflammation. Particularly, established results view AhR as a downstream target of inflammatory molecules, since its transcription is regulated by the inflammatory cascade. Interleukin 6 (IL-6) has been described to sustain early stages of inflammation and to influence the expression of AhR either directly, following signal transducer and activator of transcription 3 (STAT3) activation, or in combination with other inflammatory mediators, e.g., transforming growth factor-β (TGF-β). In selected inflammatory milieus, once activated, AhR interacts with its targets including the IL-6 promoter, thus originating an autoinflammatory loop. This perspective review brings together evidence that, in some IL-6-driven pathways, AhR is a downstream target that amplifies the duration and extent of inflammation. Considering that many inflammatory mediators can also trigger the activities of AhR as biosensor and activator of xenobiotics metabolism, this issue is of pivotal importance. The individual susceptibly to some environmental ligands of AhR can be probably explained by considering the individual inflammatory state, which could additionally fuel the proinflammatory activity of AhR. Thus, AhR could be considered a transductor of a dynamic, bidirectional connection between internal and external environmental stimuli and the inflammatory response.

scholarly journals Abundance and localization of human UBE3A protein isoforms

2020 ◽  
Vol 29 (18) ◽  
pp. 3021-3031 ◽  
Author(s):  
Carissa L Sirois ◽  
Judy E Bloom ◽  
James J Fink ◽  
Dea Gorka ◽  
Steffen Keller ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Embryonic Stem ◽  
Protein Isoforms ◽  
Wild Type ◽  
Neuronal Function ◽  
Ube3a Gene ◽  
Recent Case Study ◽  
The Individual ◽  
Human Isoforms

Abstract Loss of UBE3A expression, a gene regulated by genomic imprinting, causes Angelman syndrome (AS), a rare neurodevelopmental disorder. The UBE3A gene encodes an E3 ubiquitin ligase with three known protein isoforms in humans. Studies in mouse suggest that the human isoforms may have differences in localization and neuronal function. A recent case study reported mild AS phenotypes in individuals lacking one specific isoform. Here we have used CRISPR/Cas9 to generate isogenic human embryonic stem cells (hESCs) that lack the individual protein isoforms. We demonstrate that isoform 1 accounts for the majority of UBE3A protein in hESCs and neurons. We also show that UBE3A predominantly localizes to the cytoplasm in both wild type and isoform-null cells. Finally, we show that neurons lacking isoform 1 display a less severe electrophysiological AS phenotype.

Expression and function of CD105 during the onset of hematopoiesis from Flk1+ precursors

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3635-3642 ◽  
Author(s):  
Sarah K. Cho ◽  
Annie Bourdeau ◽  
Michelle Letarte ◽  
Juan Carlos Zúñiga-Pflücker
Keyword(s):  
Transforming Growth Factor ◽  
Es Cells ◽  
Embryonic Stem ◽  
Transforming Growth Factor Β ◽  
Hematopoietic Development ◽  
Mesoderm Specification ◽  
Molecular Events ◽  
Regulated Expression ◽  
And Function

Abstract During ontogeny, the hematopoietic system is established from mesoderm-derived precursors; however, molecular events regulating the onset of hematopoiesis are not well characterized. Several members of the transforming growth factor β (TGF-β) superfamily have been implicated as playing a role during mesoderm specification and hematopoiesis. CD105 (endoglin) is an accessory receptor for members of the TGF-β superfamily. Here it is reported that during the differentiation of murine embryonic stem (ES) cells in vitro, hematopoietic commitment within Flk1+ mesodermal precursor populations is characterized by CD105 expression. In particular, CD105 is expressed during the progression from the Flk1+CD45− to Flk1−CD45+ stage. The developmentally regulated expression of CD105 suggests that it may play a role during early hematopoiesis from Flk1+ precursors. To determine whether CD105 plays a functional role during early hematopoietic development, the potential of CD105-deficient ES cells to differentiate into various hematopoietic lineages in vitro was assessed. In the absence of CD105, myelopoiesis and definitive erythropoiesis were severely impaired. In contrast, lymphopoiesis appeared to be only mildly affected. Thus, these findings suggest that the regulated expression of CD105 functions to support lineage-specific hematopoietic development from Flk1+ precursors.

Phosphorylation of threonine 276 in Smad4 is involved in transforming growth factor-β-induced nuclear accumulation

2003 ◽  
Vol 285 (4) ◽  
pp. C823-C830 ◽  
Author(s):  
Bernard A. J. Roelen ◽  
Ori S. Cohen ◽  
Malay K. Raychowdhury ◽  
Deborah N. Chadee ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Phosphorylation Site ◽  
Transforming Growth Factor Β ◽  
Nuclear Accumulation ◽  
Mutant Protein ◽  
Wild Type ◽  
Type Protein ◽  
Wild Type Protein

Smad4, the common Smad, is central for transforming growth factor (TGF)-β superfamily ligand signaling. Smad4 has been shown to be constitutively phosphorylated (Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, Tamaki K, Hanai J, Heldin C-H, Miyazono K, and ten Dijke P. EMBO J 16: 5353-5362, 1997), but the site(s) of phosphorylation, the kinase(s) that performs this phosphorylation, and the significance of the phosphorylation of Smad4 are currently unknown. This report describes the identification of a consensus ERK phosphorylation site in the linker region of Smad4 at Thr276. Our data show that ERK can phosphorylate Smad4 in vitro but not Smad4 with mutated Thr276. Flag-tagged Smad4-T276A mutant protein accumulates less efficiently in the nucleus after stimulation by TGF-β and is less efficient in generating a transcriptional response than Smad4 wild-type protein. Tryptic phosphopeptide mapping identified a phosphopeptide in Smad4 wild-type protein that was absent in phosphorylated Smad4-T276A mutant protein. Our results suggest that MAP kinase can phosphorylate Thr276 of Smad4 and that phosphorylation can lead to enhanced TGF-β-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of Smad4.

Smad5 is dispensable for adult murine hematopoiesis

Blood ◽  
2006 ◽  
Vol 108 (12) ◽  
pp. 3707-3712 ◽  
Author(s):  
Sofie Singbrant ◽  
Jennifer L. Moody ◽  
Ulrika Blank ◽  
Goran Karlsson ◽  
Lieve Umans ◽  
...  
Keyword(s):  
Stem Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Conditional Knockout ◽  
Phenotypic Characterization ◽  
Normal Numbers ◽  
Hematopoietic Stem ◽  
Adult Mice ◽  
Lineage Distribution

AbstractSmad5 is known to transduce intracellular signals from bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-β (TGF-β) superfamily and are involved in the regulation of hematopoiesis. Recent findings suggest that BMP4 stimulates proliferation of human primitive hematopoietic progenitors in vitro, while early progenitors from mice deficient in Smad5 display increased self-renewal capacity in murine embryonic hematopoiesis. Here, we evaluate the role of Smad5 in the regulation of hematopoietic stem cell (HSC) fate decisions in adult mice by using an inducible MxCre-mediated conditional knockout model. Surprisingly, analysis of induced animals revealed unperturbed cell numbers and lineage distribution in peripheral blood (PB), bone marrow (BM), and the spleen. Furthermore, phenotypic characterization of the stem cell compartment revealed normal numbers of primitive lin–Sca-1+c-Kit+ (LSK) cells in Smad5–/– BM. When transplanted in a competitive fashion into lethally irradiated primary and secondary recipients, Smad5-deficient BM cells competed normally with wild-type (wt) cells, were able to provide long-term reconstitution for the hosts, and displayed normal lineage distribution. Taken together, Smad5-deficient HSCs from adult mice show unaltered differentiation, proliferation, and repopulating capacity. Therefore, in contrast to its role in embryonic hematopoiesis, Smad5 is dispensable for hematopoiesis in the adult mouse.

scholarly journals Protein tyrosine phosphatase-α amplifies transforming growth factor-β-dependent profibrotic signaling in lung fibroblasts

2020 ◽  
Vol 319 (2) ◽  
pp. L294-L311 ◽  
Author(s):  
Yael Aschner ◽  
Meghan Nelson ◽  
Matthew Brenner ◽  
Helen Roybal ◽  
Keriann Beke ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Protein Tyrosine Phosphatase ◽  
Transforming Growth Factor ◽  
Tyrosine Phosphatase ◽  
Transforming Growth Factor Β ◽  
Lung Fibroblasts ◽  
Type Ii ◽  
Wild Type

Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal, fibrosing lung disease for which treatment remains suboptimal. Fibrogenic cytokines, including transforming growth factor-β (TGF-β), are central to its pathogenesis. Protein tyrosine phosphatase-α (PTPα) has emerged as a key regulator of fibrogenic signaling in fibroblasts. We have reported that mice globally deficient in PTPα ( Ptpra−/−) were protected from experimental pulmonary fibrosis, in part via alterations in TGF-β signaling. The goal of this study was to determine the lung cell types and mechanisms by which PTPα controls fibrogenic pathways and whether these pathways are relevant to human disease. Immunohistochemical analysis of lungs from patients with IPF revealed that PTPα was highly expressed by mesenchymal cells in fibroblastic foci and by airway and alveolar epithelial cells. To determine whether PTPα promotes profibrotic signaling pathways in lung fibroblasts and/or epithelial cells, we generated mice with conditional (floxed) Ptpra alleles ( Ptpraf/f). These mice were crossed with Dermo1-Cre or with Sftpc-CreERT2 mice to delete Ptpra in mesenchymal cells and alveolar type II cells, respectively. Dermo1-Cre/ Ptpraf/f mice were protected from bleomycin-induced pulmonary fibrosis, whereas Sftpc-CreERT2 /Ptpraf/f mice developed pulmonary fibrosis equivalent to controls. Both canonical and noncanonical TGF-β signaling and downstream TGF-β-induced fibrogenic responses were attenuated in isolated Ptpra−/− compared with wild-type fibroblasts. Furthermore, TGF-β-induced tyrosine phosphorylation of TGF-β type II receptor and of PTPα were attenuated in Ptpra−/− compared with wild-type fibroblasts. The phenotype of cells genetically deficient in PTPα was recapitulated with the use of a Src inhibitor. These findings suggest that PTPα amplifies profibrotic TGF-β-dependent pathway signaling in lung fibroblasts.

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