scholarly journals Inhibitor of Differentiation (Id) Genes Are Expressed in the Steroidogenic Cells of the Ovine Ovary and Are Differentially Regulated by Members of the Transforming Growth Factor-β Family

Endocrinology ◽  
2009 ◽  
Vol 151 (3) ◽  
pp. 1247-1256 ◽  
Author(s):  
Kirsten Hogg ◽  
Sophie L. Etherington ◽  
Julia M. Young ◽  
Alan S. McNeilly ◽  
W. Colin Duncan
Keyword(s):  
Gene Expression ◽  
Transforming Growth Factor ◽  
Ovarian Follicle ◽  
Transforming Growth Factor Β ◽  
Differential Staining ◽  
Tgfβ Signaling ◽  
Specific Expression ◽  
Id Proteins ◽  
Thecal Cells

Inhibitor of differentiation (Id) proteins act during embryogenesis and development to repress gene transcription required for lineage commitment, while promoting cell growth. Growth factors belonging to the TGFβ superfamily of signaling molecules, notably the bone morphogenetic proteins (BMPs) and activin, can regulate Id expression in these tissues. Id expression and function in adult physiology is less well determined, and we hypothesized a role for Id proteins in the adult mammalian ovary. Immunohistochemistry for Id1, Id2, Id3, and Id4 in the sheep ovary revealed consistent expression in granulosa and thecal cells of ovarian follicles throughout development. In atretic follicles, Id proteins were selectively down-regulated in thecal cells (P < 0.0001). Additionally, Id1 was universally up-regulated in the cumulus cells adjacent to the oocyte. Immunohistochemistry for phospho (p)-smad 1/5/8 signaling components (stimulated by BMPs) showed a punctate pattern of expression whereas p-smad 2/3 (stimulated by activin) was ubiquitously expressed in follicles. Neither pathway, however, displayed differential staining in line with Id1 cumulus-specific expression, suggesting a more complex relationship between Id1 expression and TGFβ signaling in these cells. Nevertheless, in vitro, stimulation of ovine granulosa cells with BMP6 or activin A led to a respective increase and decrease in Id1 (P < 0.0001), Id2 (P < 0.0001), Id3 (P < 0.0001), and Id4 (P < 0.05) transcripts, and Id1 gene expression was further manipulated by the oocyte-secreted factors BMP15 and growth differentiation factor 9 (P < 0.001). These data confirm that TGFβ signaling can regulate Id gene expression in the sheep ovarian follicle and suggest a functional role for the Id family in the mammalian ovary.

scholarly journals Signalling pathways and mechanistic cues highlighted by transcriptomic analysis of primordial, primary, and secondary ovarian follicles in domestic cat

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shauna Kehoe ◽  
Katarina Jewgenow ◽  
Paul R. Johnston ◽  
Susan Mbedi ◽  
Beate C. Braun
Keyword(s):  
Gene Expression ◽  
Transforming Growth Factor ◽  
Ovarian Follicle ◽  
Mammalian Species ◽  
Expression Patterns ◽  
Ovarian Follicles ◽  
Domestic Cat ◽  
Transcriptional Analysis ◽  
Ovarian Folliculogenesis

AbstractIn vitro growth (IVG) of dormant primordial ovarian follicles aims to produce mature competent oocytes for assisted reproduction. Success is dependent on optimal in vitro conditions complemented with an understanding of oocyte and ovarian follicle development in vivo. Complete IVG has not been achieved in any other mammalian species besides mice. Furthermore, ovarian folliculogenesis remains sparsely understood overall. Here, gene expression patterns were characterised by RNA-sequencing in primordial (PrF), primary (PF), and secondary (SF) ovarian follicles from Felis catus (domestic cat) ovaries. Two major transitions were investigated: PrF-PF and PF-SF. Transcriptional analysis revealed a higher proportion in gene expression changes during the PrF-PF transition. Key influencing factors during this transition included the interaction between the extracellular matrix (ECM) and matrix metalloproteinase (MMPs) along with nuclear components such as, histone HIST1H1T (H1.6). Conserved signalling factors and expression patterns previously described during mammalian ovarian folliculogenesis were observed. Species-specific features during domestic cat ovarian folliculogenesis were also found. The signalling pathway terms “PI3K-Akt”, “transforming growth factor-β receptor”, “ErbB”, and “HIF-1” from the functional annotation analysis were studied. Some results highlighted mechanistic cues potentially involved in PrF development in the domestic cat. Overall, this study provides an insight into regulatory factors and pathways during preantral ovarian folliculogenesis in domestic cat.

scholarly journals Gene expression in mouse ovarian follicle development in vivo versus an ex vivo alginate culture system

Reproduction ◽  
2011 ◽  
Vol 142 (2) ◽  
pp. 309-318 ◽  
Author(s):  
Elizabeth M Parrish ◽  
Anaar Siletz ◽  
Min Xu ◽  
Teresa K Woodruff ◽  
Lonnie D Shea
Keyword(s):  
Gene Expression ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Expression Profiles ◽  
Ovarian Follicle ◽  
Gene Expression Profiles ◽  
Follicle Development ◽  
Α Subunit

Ovarian follicle maturation results from a complex interplay of endocrine, paracrine, and direct cell–cell interactions. This study compared the dynamic expression of key developmental genes during folliculogenesis in vivo and during in vitro culture in a 3D alginate hydrogel system. Candidate gene expression profiles were measured within mouse two-layered secondary follicles, multi-layered secondary follicles, and cumulus–oocyte complexes (COCs). The expression of 20 genes involved in endocrine communication, growth signaling, and oocyte development was investigated by real-time PCR. Gene product levels were compared between i) follicles of similar stage and ii) COCs derived either in vivo or by in vitro culture. For follicles cultured for 4 days, the expression pattern and the expression level of 12 genes were the same in vivo and in vitro. Some endocrine (cytochrome P450, family 19, subfamily A, polypeptide 1 (Cyp19a1) and inhibin βA subunit (Inhba)) and growth-related genes (bone morphogenetic protein 15 (Bmp15), kit ligand (Kitl), and transforming growth factor β receptor 2 (Tgfbr2)) were downregulated relative to in vivo follicles. For COCs obtained from cultured follicles, endocrine-related genes (inhibin α-subunit (Inha) and Inhba) had increased expression relative to in vivo counterparts, whereas growth-related genes (Bmp15, growth differentiation factor 9, and kit oncogene (Kit)) and zona pellucida genes were decreased. However, most of the oocyte-specific genes (e.g. factor in the germline α (Figla), jagged 1 (Jag1), and Nlrp5 (Mater)) were expressed in vitro at the same level and with the same pattern as in vivo-derived follicles. These studies establish the similarities and differences between in vivo and in vitro cultured follicles, guiding the creation of environments that maximize follicle development and oocyte quality.

scholarly journals Anti-Müllerian hormone: a new marker for ovarian function

Reproduction ◽  
2006 ◽  
Vol 131 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Jenny A Visser ◽  
Frank H de Jong ◽  
Joop S E Laven ◽  
Axel P N Themmen
Keyword(s):  
Transforming Growth Factor ◽  
Ovarian Function ◽  
Ovarian Follicle ◽  
Primordial Follicle ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Quantitative Aspect ◽  
Specific Expression ◽  
Differentiation Factors ◽  
Specific Expression Pattern

Anti-Müllerian hormone (AMH) is a member of the transforming growth factor β family of growth and differentiation factors. In the ovary, AMH has an inhibitory effect on primordial follicle recruitment as well as on the responsiveness of growing follicles to follicle-stimulating hormone (FSH). The ovary-specific expression pattern in granulosa cells of growing nonselected follicles makes AMH an ideal marker for the size of the ovarian follicle pool. This review summarizes recent findings concerning AMH and its role as a marker for the quantitative aspect of ovarian reserve as well as ovarian dysfunction.

scholarly journals Cartilage Oligomeric Matrix Protein–Derived Peptides Secreted by Cartilage Do Not Induce Responses Commonly Observed during Osteoarthritis

Cartilage ◽  
2020 ◽  
pp. 194760352096117
Author(s):  
Enrique Andrés Sastre ◽  
Frank Zaucke ◽  
Janneke Witte-Bouma ◽  
Gerjo J.V.M van Osch ◽  
Eric Farrell
Keyword(s):  
Gene Expression ◽  
Biological Activity ◽  
Cartilage Oligomeric Matrix Protein ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Disease Process ◽  
Transforming Growth Factor Β ◽  
Tube Formation ◽  
Catabolic Enzymes

Objective To evaluate if 3 peptides derived from the cartilage oligomeric matrix protein (COMP), which wounded zones of cartilage secrete into synovial fluid, possess biological activity and might therefore be involved in the regulation of specific aspects of joint regeneration. Methods The 3 peptides were produced by chemical synthesis and then tested in vitro for known functions of the COMP C-terminal domain from which they derive, and which are involved in osteoarthritis: transforming growth factor-β (TGF-β) signaling, vascular homeostasis, and inflammation. Results. None of the peptides affected the gene expression of COMP in osteochondral progenitor cells ( P > 0.05). We observed no effects on the vascularization potential of endothelial cells ( P > 0.05). In cultured synovium explants, no differences on the expression of catabolic enzymes or proinflammatory cytokines were found when peptides were added ( P > 0.05). Discussion and Conclusions The 3 peptides tested do not regulate TGF-β signaling, angiogenesis and vascular tube formation, or synovial inflammation in vitro and therefore most likely do not play a major role in the disease process.

scholarly journals Suppression of Transforming Growth Factor β Receptor 2 and Smad5 Is Associated with High Levels of MicroRNA miR-155 in the Oral Mucosa during Chronic Simian Immunodeficiency Virus Infection

2014 ◽  
Vol 89 (5) ◽  
pp. 2972-2978 ◽  
Author(s):  
Jeffy George ◽  
Mark G. Lewis ◽  
Rolf Renne ◽  
Joseph J. Mattapallil
Keyword(s):  
Growth Factor ◽  
Simian Immunodeficiency Virus ◽  
Transforming Growth Factor ◽  
Ectopic Expression ◽  
Transforming Growth Factor Β ◽  
Mucosal Inflammation ◽  
Tgfβ Signaling ◽  
Immunodeficiency Virus ◽  
Siv Infection

Chronic human immunodeficiency virus and simian immunodeficiency virus (HIV and SIV) infections are characterized by mucosal inflammation in the presence of anti-inflammatory cytokines such as transforming growth factor β (TGFβ). The mechanisms for refractiveness to TGFβ are not clear. Here we show that the expression of microRNA miR-155 was significantly upregulated in the oropharyngeal mucosa during chronic SIV infection and was coincident with downregulation of TGFβ receptor 2 (TGFβ-R2) and SMAD5, key TGFβ signaling genes that harbor putative target sites for miR-155. Ectopic expression of miR-155in vitrowas found to significantly downregulate TGFβ-R2 and Smad5 expression, suggesting a role for miR-155 in the suppression of TGFβ-R2 and SMAD5 genesin vivo. The downregulation of TGFβ signaling genes by miR-155 likely contributes to the nonresponsiveness to TGFβ during SIV infection and may inadvertently aid in increased immune activation during HIV and SIV infections.

scholarly journals Transforming Growth Factor β Is a Critical Regulator of Adult Human Islet Plasticity

2007 ◽  
Vol 21 (6) ◽  
pp. 1467-1477 ◽  
Author(s):  
Stephen Hanley ◽  
Lawrence Rosenberg
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Time Course ◽  
Transforming Growth Factor ◽  
Islet Cells ◽  
Collagen Gel ◽  
Transforming Growth Factor Β ◽  
Human Islets ◽  
Tgfβ Signaling ◽  
Vitro Model

Abstract Tissue plasticity is well documented in the context of pancreatic regeneration and carcinogenesis, with recent reports implicating dedifferentiated islet cells both as endocrine progenitors and as the cell(s) of origin in pancreatic adenocarcinoma. Accordingly, it is noteworthy that accumulating evidence suggests that TGFβ signaling is essential to pancreatic endocrine development and maintenance, whereas its loss is associated with the progression to pancreatic adenocarcinoma. The aim of this study was to examine the role of TGFβ in an in vitro model of islet morphogenetic plasticity. Human islets were embedded in a collagen gel and cultured under conditions that induced transformation into duct-like epithelial structures (DLS). Addition of TGFβ caused a dose-dependent decrease in DLS formation. Although it was demonstrated that collagen-embedded islets secrete low levels of TGFβ, antibody-mediated neutralization of this endogenously released TGFβ improved DLS formation rates, suggesting local TGFβ concentrations may in fact be higher. Time course studies indicated that TGFβ signaling was associated with an increase in ERK and p38 MAPK phosphorylation, although inhibitor-based studies were consistent with an islet endocrine-stabilizing effect mediated by p38 alone. Localization of TGFβ signaling molecules suggested that the action of TGFβ is directly on the β-cell to inhibit apoptosis and thus stabilize endocrine phenotype.

PGE2 induces angiogenesis via MT1-MMP–mediated activation of the TGFβ/Alk5 signaling pathway

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1120-1128 ◽  
Author(s):  
Arántzazu Alfranca ◽  
Juan Manuel López-Oliva ◽  
Laura Genís ◽  
Dolores López-Maderuelo ◽  
Isabel Mirones ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Kinase Activity ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
In Vivo Models ◽  
Latent Form

Abstract The development of a new vascular network is essential for the onset and progression of many pathophysiologic processes. Cyclooxygenase-2 displays a proangiogenic activity in in vitro and in vivo models, mediated principally through its metabolite prostaglandin E2 (PGE2). Here, we provide evidence for a novel signaling route through which PGE2 activates the Alk5-Smad3 pathway in endothelial cells. PGE2 induces Alk5-dependent Smad3 nuclear translocation and DNA binding, and the activation of this pathway involves the release of active TGFβ from its latent form through a process mediated by the metalloproteinase MT1-MMP, whose membrane clustering is promoted by PGE2. MT1-MMP–dependent transforming growth factor β (TGFβ) signaling through Alk5 is also required for PGE2-induced endothelial cord formation in vitro, and Alk5 kinase activity is required for PGE2-induced neovascularization in vivo. These findings identify a novel signaling pathway linking PGE2 and TGFβ, 2 effectors involved in tumor growth and angiogenesis, and reveal potential targets for the treatment of angiogenesis-related disorders.

Human bronchial epithelial cell transcriptome: gene expression changes following acute exposure to whole cigarette smoke in vitro

2007 ◽  
Vol 292 (5) ◽  
pp. L1248-L1256 ◽  
Author(s):  
Heather Maunders ◽  
Sudhanshu Patwardhan ◽  
Jeremy Phillips ◽  
Aaron Clack ◽  
Audrey Richter
Keyword(s):  
Gene Expression ◽  
Cigarette Smoke ◽  
Cell Biology ◽  
Transforming Growth Factor ◽  
Expression Profiles ◽  
Complex Mixture ◽  
Gene Expression Profiles ◽  
Transforming Growth Factor Β ◽  
Lung Epithelial Cells

Cigarette smoke is a complex mixture of more than 4,000 constituents. Its effects on cell biology are poorly understood, partly because whole smoke exposure in vitro is technically challenging. To investigate the effects of smoke on cell signaling and function, a three-dimensional air-liquid interface model of tracheobronchial epithelium, grown from primary human lung epithelial cells, was exposed to air or whole mainstream cigarette smoke for 1 h in a purpose-designed chamber. Gene expression profiles were then determined at 1, 6, and 24 h postexposure using Affymetrix HGU133-2 Plus microarrays. Cells from three different donors were used in the study, and the experiment was performed in triplicate for each donor. Genes significantly regulated by smoke, compared with the air control, in all experiments were determined. Genes exhibiting differential expression were assigned to functional categories and mapped to signaling pathways. Effects were observed on many cellular processes including xenobiotic metabolism, oxidant/antioxidant balance, and DNA damage and repair. Notably, there was marked downregulation of the transforming growth factor-β pathway, which has not been previously reported. This study provides important data on the acute effects of whole cigarette smoke on mucociliary epithelium and may be used to gain a greater understanding of smoke toxicity.

scholarly journals Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Andrea-Hermina Györfi ◽  
Alexandru-Emil Matei ◽  
Maximilian Fuchs ◽  
Chunguang Liang ◽  
Aleix Rius Rigau ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Myofibroblast Differentiation ◽  
Dependent Manner ◽  
Cytoskeleton Organization ◽  
Fibrotic Diseases ◽  
Sp Transcription Factors

Transforming growth factor-β (TGFβ) is a key mediator of fibroblast activation in fibrotic diseases, including systemic sclerosis. Here we show that Engrailed 1 (EN1) is reexpressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFβ signaling in myofibroblast differentiation: TGFβ induces EN1 expression in a SMAD3-dependent manner, and in turn, EN1 mediates the profibrotic effects of TGFβ. RNA sequencing demonstrates that EN1 induces a profibrotic gene expression profile functionally related to cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the reorganization of cytoskeleton during myofibroblast differentiation, in both standard fibroblast culture systems and in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.

scholarly journals Overexpression of ubiquitin-specific peptidase 15 in systemic sclerosis fibroblasts increases response to transforming growth factor β

Rheumatology ◽  
2019 ◽  
Vol 58 (4) ◽  
pp. 708-718
Author(s):  
Christine Galant ◽  
Joel Marchandise ◽  
Maria S Stoenoiu ◽  
Julie Ducreux ◽  
Aurélie De Groof ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Transforming Growth Factor ◽  
Cell Metabolism ◽  
Fibroblast Cell ◽  
Transforming Growth Factor Β ◽  
Primary Fibroblast ◽  
Skin Biopsies ◽  
Fibroblast Cell Lines

Abstract Objective Ubiquitination of proteins leads to their degradation by the proteasome, and is regulated by ubiquitin ligases and substrate-specific ubiquitin-specific peptidases (USPs). The ubiquitination process also plays important roles in the regulation of cell metabolism and cell cycle. Here, we found that the expression of several USPs is increased in SSc tenosynovial and skin biopsies, and we demonstrated that USP inhibition decreases TGF-β signalling in primary fibroblast cell lines. Methods High-density transcriptomic studies were performed using total RNA obtained from SSc tenosynovial samples. Confirmatory immunostaining experiments were performed on tenosynovial and skin samples. In vitro experiments were conducted in order to study the influence of USP modulation on responses to TGF-β stimulation. Results Tenosynovial biopsies from SSc patients overexpressed known disease-associated gene pathways: fibrosis, cytokines and chemokines, and Wnt/TGF-β signalling, but also several USPs. Immunohistochemistry experiments confirmed the detection of USPs in the same samples, and in SSc skin biopsies. Exposure of primary fibroblast cell lines to TGF-β induced USP gene expression. The use of a pan-USP inhibitor decreased SMAD3 phosphorylation, and expression of COL1A1, COL3A1 and fibronectin gene expression in TGF-β-stimulated fibroblasts. The effect of the USP inhibitor resulted in increased SMAD3 ubiquitination, and was blocked by a proteasome inhibitor, thereby confirming the specificity of its action. Conclusion Overexpression of several USPs, including USP15, amplifies fibrotic responses induced by TGF-β, and is a potential therapeutic target in SSc.

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