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Qiang Zhang, Yaqing Zhang, Joshua D Parsels, Ines Lohse, Theodore S Lawrence, Marina Pasca di Magliano, Yi Sun, Meredith A Morgan
Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-Kras(G12D);Fbxw7(fl/fl) (KFC(fl/fl)) compound mice. We found that KFC(fl/fl) mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age...
October 17, 2016: Neoplasia: An International Journal for Oncology Research
Ruijie Liu, Hadi Khalil, Suh-Chin J Lin, Michelle A Sargent, Allen J York, Jeffery D Molkentin
Nemo-like kinase (NLK) is an evolutionary conserved serine/threonine protein kinase implicated in development, proliferation and apoptosis regulation. Here we identified NLK as a gene product induced in the hearts of mice subjected to pressure overload or myocardial infarction injury, suggesting a potential regulatory role with pathological stimulation to this organ. To examine the potential functional consequences of increased NLK levels, cardiac-specific transgenic mice with inducible expression of this gene product were generated, as well as cardiac-specific Nlk gene-deleted mice...
2016: PloS One
Kun Yang, Yun Gao, Mingfu Yang, Zuoshang Xu, Qian Chen
Because the function of most non-coding (nc) RNAs is unknown, Cre-lox transgenic mice are useful tools to determine their functions in a tissue or developmental stage-specific manner. However, the technology faces challenges because expression of ncRNA-transgene lacks protein product. No antibody or peptide-tag can be used to trace ncRNA expression in mouse tissues in real time. Furthermore, transgene integration at different locus or orientations in the genome may result in recombination of genomic fragments in the Cre-lox system...
October 20, 2016: Connective Tissue Research
Thomas Viereckel, Sylvie Dumas, Casey J A Smith-Anttila, Bianca Vlcek, Zisis Bimpisidis, Malin C Lagerström, Åsa Konradsson-Geuken, Åsa Wallén-Mackenzie
The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson's disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies...
October 20, 2016: Scientific Reports
Sieglinde Bayer, Matthias Wirth
The protein sequences of class I HDACs in mice and humans are 96-99 % identical. These highly conserved proteins have crucial roles in biological processes, such as proliferation and development, which is reflected in the lethality that occurs in conventional whole body knockout mice. Therefore, conditional knockouts are inevitable to investigate the functions of class I HDACs in mice. Here, we describe the generation of conditional class I Hdac knockout mice, using Hdac1 as an example. We explain a relatively quick procedure to generate the necessary target vectors by recombination-mediated genetic engineering and gateway techniques...
2017: Methods in Molecular Biology
Laurel L Ballantyne, Yuan Yan Sin, Osama Y Al-Dirbashi, Xinzhi Li, David J Hurlbut, Colin D Funk
Arginase-1 (Arg1) converts arginine to urea and ornithine in the distal step of the urea cycle in liver. We previously generated a tamoxifen-inducible Arg1 deficient mouse model (Arg1-Cre) that disrupts Arg1 expression throughout the whole body and leads to lethality ≈ 2 weeks after gene disruption. Here, we evaluate if liver-selective Arg1 loss is sufficient to recapitulate the phenotype observed in global Arg1 knockout mice, as well as to gauge the effectiveness of gene delivery or hepatocyte transplantation to rescue the phenotype...
December 2016: Molecular Genetics and Metabolism Reports
Qifang Long, Weipei Zhu, Jundong Zhou, Jinchang Wu, Weixian Lu, Cui Zheng, Dongmei Zhou, Ling Yu, Ru Yang
Ovarian cancer is one of the most lethal malignant gynecologic tumors with a high relapse rate worldwide. Cancer stem cells (CSC) have been identified in ovarian cancer and other malignant tumors as a small population of cells that are capable of self-renew and multi-differentiation. CD133 positive (CD133(+)) ovarian cancer stem cells have been reported to be more tumorigenic and more resistant to chemotherapeutic treatment. Thus, CD133 has emerged as one of the most promising therapeutic markers for ovarian cancer treatment...
October 18, 2016: Oncology Research
Sybille Koehler, Sebastian Brähler, Alexander Kuczkowski, Julia Binz, Matthias J Hackl, Henning Hagmann, Martin Höhne, Merly C Vogt, Claudia M Wunderlich, F Thomas Wunderlich, Frank Schweda, Bernhard Schermer, Thomas Benzing, Paul T Brinkkoetter
Chronic alterations in calcium (Ca(2+)) signalling in podocytes have been shown to cause proteinuria and progressive glomerular diseases. However, it is unclear whether short Ca(2+) peaks influence glomerular biology and cause podocyte injury. Here we generated a DREADD (Designer Receptor Exclusively Activated by a Designer Drug) knock-in mouse line to manipulate intracellular Ca(2+) levels. By mating to a podocyte-specific Cre driver we are able to investigate the impact of Ca(2+) peaks on podocyte biology in living animals...
October 19, 2016: Scientific Reports
Elizabeth M Todd, Julie Y Zhou, Taylor P Szasz, Lauren E Deady, June A D'Angelo, Matthew D Cheung, Alfred H J Kim, Sharon Celeste Morley
Alveolar macrophages are lung-resident sentinel cells that develop perinatally and protect against pulmonary infection. Molecular mechanisms controlling alveolar macrophage generation have not been fully defined. Here we show that the actin-bundling protein L-plastin (LPL) is required for the perinatal development of alveolar macrophages. Mice expressing a conditional allele of LPL (CD11c.Cre(pos)-LPL(fl/fl)) exhibited significant reductions in alveolar macrophages and failed to effectively clear pulmonary pneumococcal infection, showing that immunodeficiency results from reduced alveolar macrophage numbers...
October 6, 2016: Blood
Minhan Ka, Jeffrey J Moffat, Woo-Yang Kim
GABAergic interneurons develop in the ganglionic eminence in the ventral telencephalon and tangentially migrate into the cortical plate during development. However, key molecules controlling interneuron migration remain poorly identified. Here, we show that microtubule-actin cross-linking factor 1 (MACF1) regulates GABAergic interneuron migration and positioning in the developing mouse brain. To investigate the role of MACF1 in developing interneurons, we conditionally deleted the MACF1 gene in mouse interneuron progenitors and their progeny using Dlx5/6-Cre-IRES-EGFP and Nkx2...
October 18, 2016: Cerebral Cortex
Sandip K Boss, Irina Hutson, Charles Harris
Exogenous glucocorticoid (GC) administration results in hyperglycemia, insulin resistance, hepatic dyslipidemia and hypertension, a constellation of findings known as Cushing's syndrome. These effects are mediated by the glucocorticoid receptor (GR). Since GR activation in liver and adipose has been implicated in metabolic syndrome we wanted to determine the role of GR in these tissues in the development of metabolic syndrome. Since GRKO mice (whole body KO) exhibit perinatal lethality due to respiratory failure, we generated tissue specific (liver or adipose) GRKO mice using cre-lox technology...
October 18, 2016: Endocrinology
David Harrison
Hypertension remains an enormous health care burden that affects one third of the population. Despite its prevalence the cause of most cases of hypertension remains unknown. Our laboratory has defined a novel mechanism for hypertension involving adaptive immunity. We found that mice lacking lymphocytes (RAG-1 mice) develop blunted hypertensive responses to a variety of stimuli including chronic angiotensin II infusion, DOCA-salt challenge and norepinephrine infusion. Adoptive transfer of T cells, but not B cells, restores the hypertensive responses to these stimuli...
September 2016: Journal of Hypertension
Toshifumi Nakamura, Isao Kurihara, Sakiko Kobayashi, Kenichi Yokota, Ayano Murai-Takeda, Yuko Mitsuishi, Mitsuha Morisaki, Nao Kohata, Yosuke Oshima, Gunther Schutz, Hirotaka Shibata, Hiroshi Itoh
OBJECTIVE: Recent studies have unveiled cardiovascular pathological roles of mineralocorticoid receptor (MR) in many types of cells. Although we have confirmed high expression of MR in intestinal epithelial cells (IEC), that role in progression of cardiovascular diseases is yet to be elucidated. As intestine is the first gate sensing sodium intake, MR of this organ is expected to have essential roles in blood pressure (BP) regulation. This study investigated the role of MR in IEC by using IEC-specific MR knockout mice (IEC-MR KO)...
September 2016: Journal of Hypertension
Ernesto Schiffrin
For many years we have studied models of hypertension in which endothelin-1 (ET-1) is overexpressed. These include DOCA-salt hypertensive rats, Dahl-salt sensitive rats, and stroke prone SHR, in all of which ET-1-mediated mechanisms play a role in blood pressure elevation and vascular injury. In humans we demonstrated overexpression of ET-1 in the endothelium of small arteries from stage 2 hypertensive patients. We have also produced a mouse that overexpresses human ET-1 in the endothelium using a Tie-2 promoter, which exhibited increased oxidative stress and inflammation, hypertrophic remodeling and endothelial dysfunction of small arteries but only slight blood pressure elevation...
September 2016: Journal of Hypertension
Pierre Paradis, Suellen C Coelho, Sofiane Ouerd, Júlio C Fraulob-Aquino, Stefan Offermanns, Ernesto L Schiffrin
OBJECTIVE: The mechanisms of blood pressure (BP) regulation by endothelin (ET)-1 produced by endothelial cells are complex and remain unclear. Recently, we developed a transgenic mouse with tamoxifen-inducible endothelium-restricted human ET-1 overexpression (ieET-1) using Cre/loxP technology. ieET-1 mice exhibited a BP increase after three weeks of induction in an ET type A receptor-dependent manner, in absence of evident vascular injury. It is unknown whether long-term exposure to ET-1 overexpression results in persistent BP elevation and vascular injury...
September 2016: Journal of Hypertension
George S Vidal, Maja Djurisic, Kiana Brown, Richard W Sapp, Carla J Shatz
Synapse density on cortical pyramidal neurons is modulated by experience. This process is highest during developmental critical periods, when mechanisms of synaptic plasticity are fully engaged. In mouse visual cortex, the critical period for ocular dominance (OD) plasticity coincides with the developmental pruning of synapses. At this time, mice lacking paired Ig-like receptor B (PirB) have excess numbers of dendritic spines on L5 neurons; these spines persist and are thought to underlie the juvenile-like OD plasticity observed in adulthood...
September 2016: ENeuro
Kaname Uno, Katsunori Iijima, Yasuhiko Abe, Tomoyuki Koike, Yasushi Takahashi, Nobuyuki Ara, Tooru Shimosegawa
PURPOSE: Endoscopic diagnosis of gastric cancer (GC) that emerges after eradication of Helicobacter pylori may be affected by unique morphological changes. Using comprehensive endoscopic imaging, which can reveal biological alterations in gastric mucosa after eradication, previous studies demonstrated that Congo red chromoendoscopy (CRE) might clearly show an acid non-secretory area (ANA) with malignant potential, while autofluorescence imaging (AFI) without drug injection or dyeing may achieve early detection or prediction of GC...
September 2016: Journal of Gastric Cancer
Cristina Villa Del Campo, Ghislaine Lioux, Rita Carmona, Rocío Sierra, Ramón Muñoz-Chápuli, Cristina Clavería, Miguel Torres
Myc is an essential regulator of cell growth and proliferation. Myc overexpression promotes the homeostatic expansion of cardiomyocyte populations by cell competition, however whether this applies to other cardiac lineages remains unknown. The epicardium contributes signals and cells to the developing and adult injured heart and exploring strategies for modulating its activity is of great interest. Using inducible genetic mosaics, we overexpressed Myc in the epicardium and determined the differential expansion of Myc-overexpressing cells with respect to their wild type counterparts...
October 18, 2016: Scientific Reports
Gang Chen, Paul A Taylor, Yong-Wook Shin, Richard C Reynolds, Robert W Cox
It has been argued that naturalistic conditions in FMRI studies provide a useful paradigm for investigating perception and cognition through a synchronization measure, inter-subject correlation (ISC). However, one analytical stumbling block has been the fact that the ISC values associated with each single subject are not independent, and our previous paper (Chen et al., 2016) used simulations and analyses of real data to show that the methodologies adopted in the literature do not have the proper control for false positives...
October 14, 2016: NeuroImage
Gry Fluge Vindedal, Anna E Thoren, Vidar Jensen, Arne Klungland, Yong Zhang, Michael J Holtzman, Ole Petter Ottersen, Erlend A Nagelhus
There is a constitutive production of water in brain. The efflux routes of this excess water remain to be identified. We used basal brain water content as a proxy for the capacity of water exit routes. Basal brain water content was increased in mice with a complete loss of aquaporin-4 (AQP4) water channels (global Aqp4(-/-) mice), but not in mice with a selective removal of perivascular AQP4 or in a novel mouse line with a selective deletion of ependymal AQP4 (Foxj1-Cre-Aqp4(flox/flox) mice). Unique for the global Aqp4(-/-) mice is the loss of the AQP4 pool subjacent to the pial membrane...
October 14, 2016: Molecular and Cellular Neurosciences
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