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Loss of flow responsive Tie1 results in Impaired
Aortic valve remodeling.
Qu X, Violette K, Sewell-Loftin MK, Soslow J, Saint-Jean L, Hinton RB, Merryman WD, Baldwin HS
(2019) Dev Biol 455: 73-84
MeSH Terms: Animals, Aortic Valve, Endothelial Cells, Extracellular Matrix, Female, Gene Expression Profiling, Gene Expression Regulation, Developmental, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Organogenesis, Pregnancy, Receptor, TIE-1, SOX9 Transcription Factor, Vascular Remodeling
Show Abstract · Added November 25, 2019
The mechanisms regulating endothelial cell response to hemodynamic forces required for heart valve development, especially valve remodeling, remain elusive. Tie1, an endothelial specific receptor tyrosine kinase, is up-regulated by oscillating shear stress and is required for lymphatic valve development. In this study, we demonstrate that valvular endothelial Tie1 is differentially expressed in a dynamic pattern predicted by disturbed flow during valve remodeling. Following valvular endocardial specific deletion of Tie1 in mice, we observed enlarged aortic valve leaflets, decreased valve stiffness and valvular insufficiency. Valve abnormalities were only detected in late gestation and early postnatal mutant animals and worsened with age. The mutant mice developed perturbed extracellular matrix (ECM) deposition and remodeling characterized by increased glycosaminoglycan and decreased collagen content, as well as increased valve interstitial cell expression of Sox9, a transcription factor essential for normal ECM maturation during heart valve development. This study provides the first evidence that Tie1 is involved in modulation of late valve remodeling and suggests that an important Tie1-Sox9 signaling axis exists through which disturbed flows are converted by endocardial cells to paracrine Sox9 signals to modulate normal matrix remodeling of the aortic valve.
Copyright © 2019. Published by Elsevier Inc.
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15 MeSH Terms
The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis.
Tsuda M, Fukuda A, Roy N, Hiramatsu Y, Leonhardt L, Kakiuchi N, Hoyer K, Ogawa S, Goto N, Ikuta K, Kimura Y, Matsumoto Y, Takada Y, Yoshioka T, Maruno T, Yamaga Y, Kim GE, Akiyama H, Ogawa S, Wright CV, Saur D, Takaori K, Uemoto S, Hebrok M, Chiba T, Seno H
(2018) J Clin Invest 128: 3475-3489
MeSH Terms: Animals, Carcinoma, Pancreatic Ductal, Cell Transformation, Neoplastic, DNA Helicases, Female, Gene Expression Regulation, Humans, Male, Mice, Mice, Transgenic, Nuclear Proteins, Pancreatic Neoplasms, Response Elements, SOX9 Transcription Factor, Signal Transduction, Transcription Factors, Tumor Suppressor Protein p53
Show Abstract · Added August 7, 2018
Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.
2 Communities
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17 MeSH Terms
Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas.
Liu Y, Sethi NS, Hinoue T, Schneider BG, Cherniack AD, Sanchez-Vega F, Seoane JA, Farshidfar F, Bowlby R, Islam M, Kim J, Chatila W, Akbani R, Kanchi RS, Rabkin CS, Willis JE, Wang KK, McCall SJ, Mishra L, Ojesina AI, Bullman S, Pedamallu CS, Lazar AJ, Sakai R, Cancer Genome Atlas Research Network, Thorsson V, Bass AJ, Laird PW
(2018) Cancer Cell 33: 721-735.e8
MeSH Terms: Adenocarcinoma, Aneuploidy, Chromosomal Instability, DNA Methylation, DNA Polymerase II, DNA-Binding Proteins, Epigenesis, Genetic, Female, Gastrointestinal Neoplasms, Gene Regulatory Networks, Heterogeneous-Nuclear Ribonucleoproteins, Humans, Male, Microsatellite Instability, MutL Protein Homolog 1, Mutation, Poly-ADP-Ribose Binding Proteins, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins p21(ras), RNA-Binding Proteins, SOX9 Transcription Factor
Show Abstract · Added October 30, 2019
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.
Copyright © 2018 Elsevier Inc. All rights reserved.
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21 MeSH Terms
ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice.
Kimura Y, Fukuda A, Ogawa S, Maruno T, Takada Y, Tsuda M, Hiramatsu Y, Araki O, Nagao M, Yoshikawa T, Ikuta K, Yoshioka T, Wang Z, Akiyama H, Wright CV, Takaori K, Uemoto S, Chiba T, Seno H
(2018) Gastroenterology 155: 194-209.e2
MeSH Terms: Adenocarcinoma in Situ, Animals, Carcinogenesis, Carcinoma, Pancreatic Ductal, Cell Culture Techniques, Cell Differentiation, DNA-Binding Proteins, Mice, Nuclear Proteins, Pancreatic Ducts, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), SOX9 Transcription Factor, Transcription Factors
Show Abstract · Added April 3, 2018
BACKGROUND & AIMS - The ARID1A gene encodes a protein that is part of the large adenosine triphosphate (ATP)-dependent chromatin remodeling complex SWI/SNF and is frequently mutated in human pancreatic ductal adenocarcinomas (PDACs). We investigated the functions of ARID1A during formation of PDACs in mice.
METHODS - We performed studies with Ptf1a-Cre;Kras mice, which express activated Kras in the pancreas and develop pancreatic intraepithelial neoplasias (PanINs), as well as those with disruption of Aird1a (Ptf1a-Cre;Kras;Arid1a mice) or disruption of Brg1 (encodes a catalytic ATPase of the SWI/SNF complex) (Ptf1a-Cre;Kras; Brg1mice). Pancreatic ductal cells (PDCs) were isolated from Arid1a mice and from Arid1a;SOX9OE mice, which overexpress human SOX9 upon infection with an adenovirus-expressing Cre recombinase. Pancreatic tissues were collected from all mice and analyzed by histology and immunohistochemistry; cells were isolated and grown in 2-dimensional and 3-dimensional cultures. We performed microarray analyses to compare gene expression patterns in intraductal papillary mucinous neoplasms (IPMNs) from the different strains of mice. We obtained 58 samples of IPMNs and 44 samples of PDACs from patients who underwent pancreatectomy in Japan and analyzed them by immunohistochemistry.
RESULTS - Ptf1a-Cre;Kras mice developed PanINs, whereas Ptf1a-Cre;Kras;Arid1a mice developed IPMNs and PDACs; IPMNs originated from PDCs. ARID1A-deficient IPMNs did not express SOX9. ARID1A-deficient PDCs had reduced expression of SOX9 and dedifferentiated in culture. Overexpression of SOX9 in these cells allowed them to differentiate and prevented dilation of ducts. Among mice with pancreatic expression of activated Kras, those with disruption of Arid1a developed fewer PDACs from IPMNs than mice with disruption of Brg1. ARID1A-deficient IPMNs had reduced activity of the mTOR pathway. Human IPMN and PDAC specimens had reduced levels of ARID1A, SOX9, and phosphorylated S6 (a marker of mTOR pathway activation). Levels of ARID1A correlated with levels of SOX9 and phosphorylated S6.
CONCLUSIONS - ARID1A regulates expression of SOX9, activation of the mTOR pathway, and differentiation of PDCs. ARID1A inhibits formation of PDACs from IPMNs in mice with pancreatic expression of activated KRAS and is down-regulated in IPMN and PDAC tissues from patients.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
2 Communities
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14 MeSH Terms
Feedback control of growth, differentiation, and morphogenesis of pancreatic endocrine progenitors in an epithelial plexus niche.
Bankaitis ED, Bechard ME, Wright CV
(2015) Genes Dev 29: 2203-16
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Cycle, Cell Differentiation, Endocrine Cells, Epithelial Cells, Feedback, Physiological, Mice, Nerve Tissue Proteins, Organogenesis, Pancreas, Receptors, Notch, SOX9 Transcription Factor, Stem Cells
Show Abstract · Added November 3, 2015
In the mammalian pancreas, endocrine cells undergo lineage allocation upon emergence from a bipotent duct/endocrine progenitor pool, which resides in the "trunk epithelium." Major questions remain regarding how niche environments are organized within this epithelium to coordinate endocrine differentiation with programs of epithelial growth, maturation, and morphogenesis. We used EdU pulse-chase and tissue-reconstruction approaches to analyze how endocrine progenitors and their differentiating progeny are assembled within the trunk as it undergoes remodeling from an irregular plexus of tubules to form the eventual mature, branched ductal arbor. The bulk of endocrine progenitors is maintained in an epithelial "plexus state," which is a transient intermediate during epithelial maturation within which endocrine cell differentiation is continually robust and surprisingly long-lived. Within the plexus, local feedback effects derived from the differentiating and delaminating endocrine cells nonautonomously regulate the flux of endocrine cell birth as well as proliferative growth of the bipotent cell population using Notch-dependent and Notch-independent influences, respectively. These feedback effects in turn maintain the plexus state to ensure prolonged allocation of endocrine cells late into gestation. These findings begin to define a niche-like environment guiding the genesis of the endocrine pancreas and advance current models for how differentiation is coordinated with the growth and morphogenesis of the developing pancreatic epithelium.
© 2015 Bankaitis et al.; Published by Cold Spring Harbor Laboratory Press.
1 Communities
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14 MeSH Terms
A Gene Regulatory Network Cooperatively Controlled by Pdx1 and Sox9 Governs Lineage Allocation of Foregut Progenitor Cells.
Shih HP, Seymour PA, Patel NA, Xie R, Wang A, Liu PP, Yeo GW, Magnuson MA, Sander M
(2015) Cell Rep 13: 326-36
MeSH Terms: Animals, Cell Lineage, Embryonic Stem Cells, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Homeodomain Proteins, Intestinal Mucosa, Intestines, Mice, Pancreas, SOX9 Transcription Factor, Trans-Activators, Transcriptional Activation
Show Abstract · Added November 3, 2015
The generation of pancreas, liver, and intestine from a common pool of progenitors in the foregut endoderm requires the establishment of organ boundaries. How dorsal foregut progenitors activate pancreatic genes and evade the intestinal lineage choice remains unclear. Here, we identify Pdx1 and Sox9 as cooperative inducers of a gene regulatory network that distinguishes the pancreatic from the intestinal lineage. Genetic studies demonstrate dual and cooperative functions for Pdx1 and Sox9 in pancreatic lineage induction and repression of the intestinal lineage choice. Pdx1 and Sox9 bind to regulatory sequences near pancreatic and intestinal differentiation genes and jointly regulate their expression, revealing direct cooperative roles for Pdx1 and Sox9 in gene activation and repression. Our study identifies Pdx1 and Sox9 as important regulators of a transcription factor network that initiates pancreatic fate and sheds light on the gene regulatory circuitry that governs the development of distinct organs from multi-lineage-competent foregut progenitors.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
1 Communities
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13 MeSH Terms
Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj.
Walter TJ, Vanderpool C, Cast AE, Huppert SS
(2014) Am J Pathol 184: 1479-88
MeSH Terms: Animals, Bile Ducts, Intrahepatic, Epithelial Cells, Hepatocyte Nuclear Factor 6, Hepatocytes, Imaging, Three-Dimensional, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Immunohistochemistry, Keratin-19, Mice, Knockout, Plant Lectins, Portal Vein, Receptors, Notch, Regeneration, SOX9 Transcription Factor
Show Abstract · Added May 27, 2014
The potential for intrahepatic bile duct (IHBD) regeneration in patients with bile duct insufficiency diseases is poorly understood. Notch signaling and Hnf6 have each been shown to be important for the morphogenesis of IHBDs in mice. One congenital pediatric liver disease characterized by reduced numbers of IHBDs, Alagille syndrome, is associated with mutations in Notch signaling components. Therefore, we investigated whether liver cell plasticity could contribute to IHBD regeneration in mice with disruptions in Notch signaling and Hnf6. We studied a mouse model of bile duct insufficiency with liver epithelial cell-specific deficiencies in Hnf6 and Rbpj, a mediator of canonical Notch signaling. Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice initially developed no peripheral bile ducts. The evolving postnatal liver phenotype was analyzed using IHBD resin casting, immunostaining, and serum chemistry. With age, Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice mounted a ductular reaction extending through the hepatic tissue and then regenerated communicating peripheral IHBD branches. Rbpj and Hnf6 were determined to remain absent from biliary epithelial cells constituting the ductular reaction and the regenerated peripheral IHBDs. We report the expression of Sox9, a marker of biliary epithelial cells, in cells expressing hepatocyte markers. Tissue analysis indicates that reactive ductules did not arise directly from preexisting hilar IHBDs. We conclude that liver cell plasticity is competent for regeneration of IHBDs independent of Notch signaling via Rbpj and Hnf6.
Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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15 MeSH Terms
Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.
Hancock DB, Soler Artigas M, Gharib SA, Henry A, Manichaikul A, Ramasamy A, Loth DW, Imboden M, Koch B, McArdle WL, Smith AV, Smolonska J, Sood A, Tang W, Wilk JB, Zhai G, Zhao JH, Aschard H, Burkart KM, Curjuric I, Eijgelsheim M, Elliott P, Gu X, Harris TB, Janson C, Homuth G, Hysi PG, Liu JZ, Loehr LR, Lohman K, Loos RJ, Manning AK, Marciante KD, Obeidat M, Postma DS, Aldrich MC, Brusselle GG, Chen TH, Eiriksdottir G, Franceschini N, Heinrich J, Rotter JI, Wijmenga C, Williams OD, Bentley AR, Hofman A, Laurie CC, Lumley T, Morrison AC, Joubert BR, Rivadeneira F, Couper DJ, Kritchevsky SB, Liu Y, Wjst M, Wain LV, Vonk JM, Uitterlinden AG, Rochat T, Rich SS, Psaty BM, O'Connor GT, North KE, Mirel DB, Meibohm B, Launer LJ, Khaw KT, Hartikainen AL, Hammond CJ, Gläser S, Marchini J, Kraft P, Wareham NJ, Völzke H, Stricker BH, Spector TD, Probst-Hensch NM, Jarvis D, Jarvelin MR, Heckbert SR, Gudnason V, Boezen HM, Barr RG, Cassano PA, Strachan DP, Fornage M, Hall IP, Dupuis J, Tobin MD, London SJ
(2012) PLoS Genet 8: e1003098
MeSH Terms: Forced Expiratory Volume, Gene Expression, Genome, Human, Genome-Wide Association Study, HLA-DQ Antigens, HLA-DQ beta-Chains, Humans, Lung, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, Inwardly Rectifying, Pulmonary Disease, Chronic Obstructive, Receptors, Cell Surface, SOX9 Transcription Factor, Smoking, Vital Capacity
Show Abstract · Added February 26, 2014
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
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16 MeSH Terms
Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma.
Kopp JL, von Figura G, Mayes E, Liu FF, Dubois CL, Morris JP, Pan FC, Akiyama H, Wright CV, Jensen K, Hebrok M, Sander M
(2012) Cancer Cell 22: 737-50
MeSH Terms: Acinar Cells, Carcinoma, Pancreatic Ductal, Genes, ras, Humans, Metaplasia, Mutation, Pancreatic Neoplasms, Precancerous Conditions, SOX9 Transcription Factor
Show Abstract · Added March 20, 2014
Tumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.
Copyright © 2012 Elsevier Inc. All rights reserved.
2 Communities
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9 MeSH Terms
Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia.
Prévot PP, Simion A, Grimont A, Colletti M, Khalaileh A, Van den Steen G, Sempoux C, Xu X, Roelants V, Hald J, Bertrand L, Heimberg H, Konieczny SF, Dor Y, Lemaigre FP, Jacquemin P
(2012) Gut 61: 1723-32
MeSH Terms: Acinar Cells, Animals, Biomarkers, Tumor, Blotting, Western, Cell Transformation, Neoplastic, Cells, Cultured, Guinea Pigs, Hepatocyte Nuclear Factor 6, Humans, Metaplasia, Mice, Models, Animal, Pancreas, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, SOX9 Transcription Factor
Show Abstract · Added September 26, 2012
OBJECTIVE - Growing evidence suggests that a phenotypic switch converting pancreatic acinar cells to duct-like cells can lead to pancreatic intraepithelial neoplasia and eventually to invasive pancreatic ductal adenocarcinoma. Histologically, the onset of this switch is characterised by the co-expression of acinar and ductal markers in acini, a lesion called acinar-to-ductal metaplasia (ADM). The transcriptional regulators required to initiate ADM are unknown, but need to be identified to characterise the regulatory networks that drive ADM. In this study, the role of the ductal transcription factors hepatocyte nuclear factor 6 (HNF6, also known as Onecut1) and SRY-related HMG box factor 9 (Sox9) in ADM was investigated.
DESIGN - Expression of HNF6 and Sox9 was measured by immunostaining in normal and diseased human pancreas. The function of the factors was tested in cultured cells and in mouse models of ADM by a combination of gain and loss of function experiments.
RESULTS - Expression of HNF6 and Sox9 was ectopically induced in acinar cells in human ADM as well as in mouse models of ADM. HNF6 and, to a lesser extent, Sox9 were required for repression of acinar genes, for modulation of ADM-associated changes in cell polarity and for activation of ductal genes in metaplastic acinar cells.
CONCLUSIONS - HNF6 and Sox9 are new biomarkers of ADM and constitute candidate targets for preventive treatment in cases when ADM may lead to cancer. This work also shows that ectopic activation of transcription factors may underlie metaplastic processes occurring in other organs.
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16 MeSH Terms