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The SUMO deconjugating peptidase Smt4 contributes to the mechanism required for transition from sister chromatid arm cohesion to sister chromatid pericentromere separation.
Stephens AD, Snider CE, Bloom K
(2015) Cell Cycle 14: 2206-18
MeSH Terms: Cell Cycle Proteins, Centromere, Chromatids, Chromosomal Proteins, Non-Histone, Chromosome Segregation, DNA Topoisomerases, Type II, Endopeptidases, Lac Operon, Mitosis, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Spindle Apparatus, Sumoylation
Show Abstract · Added January 25, 2016
The pericentromere chromatin protrudes orthogonally from the sister-sister chromosome arm axis. Pericentric protrusions are organized in a series of loops with the centromere at the apex, maximizing its ability to interact with stochastically growing and shortening kinetochore microtubules. Each pericentromere loop is ∼50 kb in size and is organized further into secondary loops that are displaced from the primary spindle axis. Cohesin and condensin are integral to mechanisms of loop formation and generating resistance to outward forces from kinesin motors and anti-parallel spindle microtubules. A major unanswered question is how the boundary between chromosome arms and the pericentromere is established and maintained. We used sister chromatid separation and dynamics of LacO arrays distal to the pericentromere to address this issue. Perturbation of chromatin spring components results in 2 distinct phenotypes. In cohesin and condensin mutants sister pericentric LacO arrays separate a defined distance independent of spindle length. In the absence of Smt4, a peptidase that removes SUMO modifications from proteins, pericentric LacO arrays separate in proportion to spindle length increase. Deletion of Smt4, unlike depletion of cohesin and condensin, causes stretching of both proximal and distal pericentromere LacO arrays. The data suggest that the sumoylation state of chromatin topology adjusters, including cohesin, condensin, and topoisomerase II in the pericentromere, contribute to chromatin spring properties as well as the sister cohesion boundary.
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13 MeSH Terms
Generation of a tenascin-C-CreER2 knockin mouse line for conditional DNA recombination in renal medullary interstitial cells.
He W, Xie Q, Wang Y, Chen J, Zhao M, Davis LS, Breyer MD, Gu G, Hao CM
(2013) PLoS One 8: e79839
MeSH Terms: Animals, Aquaporin 1, Aquaporin 2, Crosses, Genetic, Cyclooxygenase 2, Female, Fibroblasts, Founder Effect, Gene Expression Regulation, Gene Knock-In Techniques, Genes, Reporter, Green Fluorescent Proteins, Integrases, Kidney Medulla, Lac Operon, Male, Mice, Mice, Transgenic, Promoter Regions, Genetic, Tamoxifen, Tenascin, Transgenes
Show Abstract · Added January 10, 2014
Renal medullary interstitial cells (RMIC) are specialized fibroblast-like cells that exert important functions in maintaining body fluid homeostasis and systemic blood pressure. Here, we generated a RMIC specific tenascin-C promoter driven inducible CreER2 knockin mouse line with an EGFP reporter. Similar as endogenous tenascin-C expression, the reporter EGFP expression in the tenascin-C-CreER2(+/-) mice was observed in the inner medulla of the kidney, and co-localized with COX2 but not with AQP2 or AQP1, suggesting selective expression in RMICs. After recombination (tenascin-C-CreER2(+/-)/ROSA26-lacZ(+/-) mice + tamoxifen), β-gal activity was restricted to the cells in the inner medulla of the kidney, and didn't co-localize with AQP2, consistent with selective Cre recombinase activity in RMICs. Cre activity was not obvious in other major organs or without tamoxifen treatment. This inducible RMIC specific Cre mouse line should therefore provide a novel tool to manipulate genes of interest in RMICs.
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22 MeSH Terms
Tie1 attenuation reduces murine atherosclerosis in a dose-dependent and shear stress-specific manner.
Woo KV, Qu X, Babaev VR, Linton MF, Guzman RJ, Fazio S, Baldwin HS
(2011) J Clin Invest 121: 1624-35
MeSH Terms: Animals, Apolipoproteins E, Atherosclerosis, Base Sequence, Cell Adhesion Molecules, DNA Primers, Disease Models, Animal, Endothelial Cells, Female, Gene Expression, Hemorheology, Lac Operon, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Nitric Oxide Synthase Type III, RNA, Messenger, Receptor, TIE-1, Signal Transduction, Stress, Mechanical, rho-Associated Kinases
Show Abstract · Added December 10, 2013
Although the response of endothelial cells to the disturbed blood flow in the vicinity of atherosclerotic lesions is known to be distinct from that elicited by nonatherogenic laminar flow, the mechanisms involved are poorly understood. Our initial studies confirmed that expression of the endothelial receptor tyrosine kinase Tie1 was evident at regions of atherogenic flow in mature animals. We therefore hypothesized that Tie1 plays a role in the endothelial response to atherogenic shear stress. Consistent with this, we found that Tie1+/- mice bred to the apoE-deficient background displayed a 35% reduction in atherosclerosis relative to Tie1+/+;Apoe-/- mice. Since deletion of Tie1 results in embryonic lethality secondary to vascular dysfunction, we used conditional and inducible mutagenesis to study the effect of endothelial-specific Tie1 attenuation on atherogenesis in Apoe-/- mice and found a dose-dependent decrease in atherosclerotic lesions. Analysis of primary aortic endothelial cells indicated that atheroprotective laminar flow decreased Tie1 expression in vitro. Attenuation of Tie1 was associated with an increase in eNOS expression and Tie2 phosphorylation. In addition, Tie1 attenuation increased IkBα expression while decreasing ICAM levels. In summary, we have found that shear stress conditions that modulate atherogenic events also regulate Tie1 expression. Therefore, Tie1 may play a novel proinflammatory role in atherosclerosis.
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22 MeSH Terms
Mature chief cells are cryptic progenitors for metaplasia in the stomach.
Nam KT, Lee HJ, Sousa JF, Weis VG, O'Neal RL, Finke PE, Romero-Gallo J, Shi G, Mills JC, Peek RM, Konieczny SF, Goldenring JR
(2010) Gastroenterology 139: 2028-2037.e9
MeSH Terms: Acute Disease, Animals, Cell Differentiation, Cell Division, Cell Lineage, Chief Cells, Gastric, Chronic Disease, Disease Models, Animal, Gastritis, Helicobacter Infections, Helicobacter felis, Lac Operon, Metaplasia, Mice, Mice, Inbred C57BL, Mice, Transgenic, Parietal Cells, Gastric, Peptides, Precancerous Conditions, Stem Cells, Stomach Neoplasms
Show Abstract · Added October 7, 2013
BACKGROUND & AIMS - Gastric cancer evolves in the setting of a pathologic mucosal milieu characterized by both loss of acid-secreting parietal cells and mucous cell metaplasias. Indeed, mucous cell metaplasia is considered the critical preneoplastic lesion for gastric cancer. Previous investigations have shown that infection of mice with Helicobacter felis or induction of acute parietal cell loss with the drug DMP-777 leads to the emergence of a type of metaplasia designated spasmolytic polypeptide-expressing metaplasia (SPEM). We have hypothesized that SPEM arises from proliferating cells in gland bases, either from a cryptic progenitor cell or by transdifferentiation of mature chief cells.
METHODS - Taking advantage of the chief cell-restricted expression of Mist1-Cre-ER(T2), we used lineage mapping to examine whether SPEM lineages were derived from chief cells in 3 independent models of induction by DMP-777 treatment, L-635 treatment, or H felis infection.
RESULTS - Treatment of mice with L-635 for 3 days led to rapid parietal cell loss, induction of a prominent inflammatory infiltrate, and emergence of SPEM. In all 3 models, SPEM developed, at least in part, from transdifferentiation of chief cells. We further found that acute parietal cell loss in the setting of inflammation (L-635 treatment) led to more rapid induction and expansion of SPEM derived from transdifferentiation of chief cells.
CONCLUSIONS - These studies provide direct evidence by lineage tracing that SPEM evolves from differentiated chief cells. Thus, mature gastric chief cells have the ability to act as cryptic progenitors and reacquire proliferative capacity within the context of mucosal injury and inflammation.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
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21 MeSH Terms
Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension.
Anderson L, Lowery JW, Frank DB, Novitskaya T, Jones M, Mortlock DP, Chandler RL, de Caestecker MP
(2010) Am J Physiol Regul Integr Comp Physiol 298: R833-42
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Bone Morphogenetic Protein 4, Cell Division, Hypertension, Pulmonary, Hypoxia, Lac Operon, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nitric Oxide Synthase Type III, Pulmonary Artery, Pulmonary Circulation, Signal Transduction
Show Abstract · Added January 5, 2011
The bone morphogenetic protein (BMP) type 2 receptor ligand, Bmp2, is upregulated in the peripheral pulmonary vasculature during hypoxia-induced pulmonary hypertension (PH). This contrasts with the expression of Bmp4, which is expressed in respiratory epithelia throughout the lung. Unlike heterozygous null Bmp4 mice (Bmp4(LacZ/+)), which are protected from the development of hypoxic PH, mice that are heterozygous null for Bmp2 (Bmp2(+/-)) develop more severe hypoxic PH than their wild-type littermates. This is associated with reduced endothelial nitric oxide synthase (eNOS) expression and activity in the pulmonary vasculature of hypoxic Bmp2(+/-) but not Bmp4(LacZ/+) mutant mice. Furthermore, exogenous BMP2 upregulates eNOS expression and activity in intrapulmonary artery and pulmonary endothelial cell preparations, indicating that eNOS is a target of Bmp2 signaling in the pulmonary vasculature. Together, these data demonstrate that Bmp2 and Bmp4 exert opposing roles in hypoxic PH and suggest that the protective effects of Bmp2 are mediated by increasing eNOS expression and activity in the hypoxic pulmonary vasculature.
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14 MeSH Terms
Dynamic patterning at the pylorus: formation of an epithelial intestine-stomach boundary in late fetal life.
Li X, Udager AM, Hu C, Qiao XT, Richards N, Gumucio DL
(2009) Dev Dyn 238: 3205-17
MeSH Terms: Animals, Embryo, Mammalian, Female, Fetal Development, Gastric Mucosa, Gene Expression Profiling, Gestational Age, Intestinal Mucosa, Intestines, Kruppel-Like Transcription Factors, Lac Operon, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oligonucleotide Array Sequence Analysis, Pregnancy, Pylorus, Stomach, Zinc Finger Protein GLI1
Show Abstract · Added June 23, 2012
In the adult mouse, distinct morphological and transcriptional differences separate stomach from intestinal epithelium. Remarkably, the epithelial boundary between these two organs is literally one cell thick. This discrete junction is established suddenly and precisely at embryonic day (E) 16.5, by sharpening a previously diffuse intermediate zone. In the present study, we define the dynamic transcriptome of stomach, pylorus, and intestinal tissues between E14.5 and E16.5. We show that establishment of this boundary is concomitant with the induction of over a thousand genes in intestinal epithelium, and these gene products provide intestinal character. Hence, we call this process intestinalization. We identify specific transcription factors (Hnf4 gamma, Creb3l3, and Tcfec) and examine signaling pathways (Hedgehog and Wnt) that may play a role in this process. Finally, we define a unique expression domain at the pylorus itself and detect novel pylorus-specific patterns for the transcription factor Gata3 and the secreted protein nephrocan.
(c) 2009 Wiley-Liss, Inc.
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19 MeSH Terms
Kidney development and gene expression in the HIF2alpha knockout mouse.
Steenhard BM, Freeburg PB, Isom K, Stroganova L, Borza DB, Hudson BG, St John PL, Zelenchuk A, Abrahamson DR
(2007) Dev Dyn 236: 1115-25
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cells, Cultured, Gene Expression Regulation, Developmental, Kidney, Kidney Transplantation, Lac Operon, Mice, Mice, Inbred Strains, Mice, Knockout, Organ Culture Techniques, RNA, Messenger, Recombinant Fusion Proteins, Tissue Distribution, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2
Show Abstract · Added December 10, 2013
The hypoxia-inducible transcription factor-2 (HIF2), a heterodimer composed of HIF2alpha and HIF1beta subunits, drives expression of genes essential for vascularization, including vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2, Flk-1). Here, we used a HIF2alpha/LacZ transgenic mouse to define patterns of HIF2alpha transcription during kidney development and maturation. Our results from embryonic heterozygotes showed HIF2alpha/LacZ expression by apparently all renal endothelial cells. At 4 weeks of age, glomerular mesangial and vascular smooth muscle cells were also positive together with endothelial cells. These expression patterns were confirmed by electron microscopy using Bluo-gal as a beta-galactosidase substrate. Small numbers of glomerular and tubular epithelial cells were also positive at all stages examined. Light and electron microscopic examination of kidneys from HIF2alpha null embryos showed no defects in renal vascular development or nephrogenesis. Similarly, the same amounts of Flk-1 protein were seen on Western blots of kidney extracts from homozygous and heterozygous HIF2alpha mutants. To examine responsiveness of HIF2alpha null kidneys to hypoxia, embryonic day 13.5 metanephroi were cultured in room air or in mild (5% O(2)) hypoxia. For both heterozygous and null samples, VEGF mRNA levels doubled when metanephroi were cultured in mild hypoxia. Anterior chamber grafts of embryonic HIF2alpha knockouts were morphologically indistinguishable from heterozygous grafts. Endothelial markers, platelet endothelial cell adhesion molecule and BsLB4, as well as glomerular epithelial markers, GLEPP1 and WT-1, were all expressed appropriately. Finally, we undertook quantitative real-time polymerase chain reaction of kidneys from HIF2alpha null embryos and wild-type siblings and found no compensatory up-regulation of HIF1alpha or -3alpha. Our results show that, although HIF2alpha was widely transcribed by kidney endothelium and vascular smooth muscle, knockouts displayed no detectable deficits in vessel development or VEGF or Flk-1 expression.
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16 MeSH Terms
Novel mouse strain with Cre recombinase in 11beta-hydroxysteroid dehydrogenase-2-expressing cells.
Náray-Fejes-Tóth A, Fejes-Tóth G
(2007) Am J Physiol Renal Physiol 292: F486-94
MeSH Terms: 11-beta-Hydroxysteroid Dehydrogenase Type 2, Aldosterone, Animals, Animals, Newborn, Brain Chemistry, Colon, Female, Immunohistochemistry, Integrases, Kidney, Kidney Tubules, Collecting, Lac Operon, Male, Mice, Mice, Transgenic, Promoter Regions, Genetic, beta-Galactosidase
Show Abstract · Added September 9, 2013
Here we describe the generation and characterization of a mouse strain that expresses an improved Cre (iCre) recombinase (48) under the control of the endogenous 11beta-hydroxysteroid dehydrogenase type 2 (11HSD2) promoter. Progeny of 11HSD2/iCre and ROSA26 reporter mice were used to determine the pattern of iCre expression by measuring the activity of the LacZ gene product beta-galactosidase in a panel of tissues. On Cre recombinase activity, intense beta-galactosidase activity (X-gal staining) was observed in the classic mineralocorticoid target segments of the kidney, as well as in the colon, and both female and male reproductive organs. Weaker iCre expression was detected in the lung and heart. In the brain, strong iCre activity was present in cardiovascular centers that are known to express 11HSD2 and mineralocorticoid receptors [nucleus tractus solitarius (NTS) and amygdala] as well as in the granular layer of the cerebellum. iCre expression was weaker in neonatal kidney and colon than in the adult but was present in the hair follicles and cartilage. These results indicate that in the 11HSD2/iCre strain iCre expression faithfully represents the expression pattern of endogenous 11HSD2. Thus this mouse model represents the first Cre deleter strain that can be used to eliminate desired genes in every mineralocorticoid target tissue. This mouse model should serve as a useful resource for investigators who want to study the function of genes involved in aldosterone action and genes in other pathways that are selectively expressed in these cells.
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17 MeSH Terms
Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression.
Brantley-Sieders DM, Fang WB, Hicks DJ, Zhuang G, Shyr Y, Chen J
(2005) FASEB J 19: 1884-6
MeSH Terms: Adenocarcinoma, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cell Survival, Cell Transplantation, Collagen, Disease Progression, Drug Combinations, Endothelium, Vascular, Ephrin-A1, Female, In Situ Nick-End Labeling, Lac Operon, Laminin, Ligands, Lung, Mammary Neoplasms, Animal, Mice, Mice, Inbred BALB C, Mice, Nude, Mice, Transgenic, Microcirculation, Microscopy, Fluorescence, Models, Biological, Models, Statistical, Mutation, Neoplasm Metastasis, Neoplasm Transplantation, Neovascularization, Pathologic, Oxygen, Phenotype, Platelet Endothelial Cell Adhesion Molecule-1, Proteoglycans, Receptor, EphA2, Receptors, Eph Family, rac1 GTP-Binding Protein
Show Abstract · Added March 5, 2014
EphA2 belongs to a unique family of receptor tyrosine kinases that play critical roles in development and disease. Since EphA2 is required for ephrin-A1 ligand-induced vascular remodeling and is overexpressed in a variety of vascularized human adenocarcinomas, we assessed tumor angiogenesis and metastatic progression in EphA2-deficient host animals. 4T1 metastatic mammary adenocarcinoma cells transplanted subcutaneously and orthotopically into EphA2-deficient female mice displayed decreased tumor volume, tumor cell survival, microvascular density, and lung metastasis relative to tumor-bearing littermate controls. To determine if the phenotype in EphA2-deficient mice was endothelial cell intrinsic, we also analyzed endothelial cells isolated from EphA2-deficient animals for their ability to incorporate into tumor vessels in vivo, as well as to migrate in response to tumor-derived signals in vitro. EphA2-deficient endothelial cells displayed impaired survival and failed to incorporate into tumor microvessels in vivo, and displayed impaired tumor-mediated migration in vitro relative to controls. These data suggest that host EphA2 receptor tyrosine kinase function is required in the tumor microenvironment for tumor angiogenesis and metastatic progression.
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38 MeSH Terms
Interactions between areas I and II direct pdx-1 expression specifically to islet cell types of the mature and developing pancreas.
Van Velkinburgh JC, Samaras SE, Gerrish K, Artner I, Stein R
(2005) J Biol Chem 280: 38438-44
MeSH Terms: Animals, Animals, Newborn, Base Sequence, Binding Sites, Cell Differentiation, Cell Line, Cell Nucleus, Chromatin, Chromatin Immunoprecipitation, DNA Mutational Analysis, Enhancer Elements, Genetic, Galactosides, Homeodomain Proteins, Humans, Immunohistochemistry, Indoles, Insulin, Insulinoma, Islets of Langerhans, Lac Operon, Mice, Molecular Sequence Data, NIH 3T3 Cells, Pancreas, Protein Binding, Protein Structure, Tertiary, Recombinant Fusion Proteins, Trans-Activators, Transcription Factors, Transcription, Genetic, Transfection, Transgenes
Show Abstract · Added August 13, 2010
PDX-1 regulates transcription of genes involved in islet beta cell function and pancreas development. Islet-specific expression is controlled by 5'-flanking sequences from base pair (bp) -2917 to -1918 in transgenic experiments, which encompasses both conserved (i.e. Area I (bp -2761/-2457), Area II (bp -2153/-1923)) and non-conserved pdx-1 sequences. However, only an Area II-driven transgene is independently active in vivo, albeit in only a fraction of islet PDX-1-producing cells. Our objective was to identify the sequences within the -2917/-1918-bp region that act in conjunction with Area II to allow comprehensive expression in islet PDX-1(+) cells. In cell line-based transfection assays, only Area I effectively potentiated Area II activity. Both Area I and Area II functioned in an orientation-independent manner, whereas synergistic, enhancer-like activation was uniquely found with duplicated Area II. Chimeras of Area II and the generally active SV40 enhancer or the beta cell-specific insulin enhancer suggested that islet cell-enriched activators were necessary for Area I activation, because Area II-mediated stimulation was reduced by the SV40 enhancer and activated by the insulin enhancer. Several conserved sites within Area I were important in Area I/Area II activation, with binding at bp -2614/-2609 specifically controlled by Nkx2.2, an insulin gene regulator that is required for terminal beta cell differentiation. The ability of Area I to modulate Area II activation was also observed in vivo, as an Area I/Area II-driven transgene recapitulated the endogenous pdx-1 expression pattern in developing and adult islet cells. These results suggest that Area II is a central pdx-1 control region, whose islet cell activity is uniquely modified by Area I regulatory factors.
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32 MeSH Terms