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https://www.readbyqxmd.com/read/28219977/adrenergic-receptors-in-individual-ventricular-myocytes-the-beta-1-and-alpha-1b-are-in-all-cells-the-alpha-1a-is-in-a-subpopulation-and-the-beta-2-and-beta-3-are-mostly-absent
#1
Bat-Erdene Myagmar, James M Flynn, Patrick M Cowley, Philip Swigart, Megan Montgomery, Kevin Thai, Divya R Nair, Rumita Gupta, Chihiro Hosoda, Simon Melov, Anthony J Baker, Paul C Simpson
Rationale: It is unknown if every ventricular myocyte expresses all 5 of the cardiac adrenergic receptors (ARs), beta-1, beta-2, beta-3, alpha-1A, and alpha-1B. The beta-1 and beta-2 are thought to be the dominant myocyte ARs. Objective: Quantify the 5 cardiac ARs in individual ventricular myocytes. Methods and Results: We studied ventricular myocytes from wild type mice, mice with alpha-1A and alpha-1B knockin reporters, and beta-1 and beta-2 knockout mice. Using individual isolated cells, we measured knockin reporters, mRNAs, signaling (phosphorylation of ERK and phospholamban), and contraction...
February 20, 2017: Circulation Research
https://www.readbyqxmd.com/read/28219395/efficient-precise-knockin-with-a-double-cut-hdr-donor-after-crispr-cas9-mediated-double-stranded-dna-cleavage
#2
Jian-Ping Zhang, Xiao-Lan Li, Guo-Hua Li, Wanqiu Chen, Cameron Arakaki, Gary D Botimer, David Baylink, Lu Zhang, Wei Wen, Ya-Wen Fu, Jing Xu, Noah Chun, Weiping Yuan, Tao Cheng, Xiao-Bing Zhang
BACKGROUND: Precise genome editing via homology-directed repair (HDR) after double-stranded DNA (dsDNA) cleavage facilitates functional genomic research and holds promise for gene therapy. However, HDR efficiency remains low in some cell types, including some of great research and clinical interest, such as human induced pluripotent stem cells (iPSCs). RESULTS: Here, we show that a double cut HDR donor, which is flanked by single guide RNA (sgRNA)-PAM sequences and is released after CRISPR/Cas9 cleavage, increases HDR efficiency by twofold to fivefold relative to circular plasmid donors at one genomic locus in 293 T cells and two distinct genomic loci in iPSCs...
February 20, 2017: Genome Biology
https://www.readbyqxmd.com/read/28215705/kras-allelic-imbalance-enhances-fitness-and-modulates-map-kinase-dependence-in-cancer
#3
Michael R Burgess, Eugene Hwang, Rana Mroue, Craig M Bielski, Anica M Wandler, Benjamin J Huang, Ari J Firestone, Amy Young, Jennifer A Lacap, Lisa Crocker, Saurabh Asthana, Elizabeth M Davis, Jin Xu, Keiko Akagi, Michelle M Le Beau, Qing Li, Benjamin Haley, David Stokoe, Deepak Sampath, Barry S Taylor, Marie Evangelista, Kevin Shannon
Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in Kras(G12D) "knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition...
February 16, 2017: Cell
https://www.readbyqxmd.com/read/28202664/lrrk2-mouse-models-dissecting-the-behavior-striatal-neurochemistry-and-neurophysiology-of-pd-pathogenesis
#4
REVIEW
Mattia Volta, Heather Melrose
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD), resembling the sporadic disorder. Intensive effort has been directed toward LRRK2 mouse modeling and investigation, aimed at reproducing the human disease to inform mechanistic studies of pathogenesis and design of neuroprotective therapies. The physiological function of LRRK2 is still under exploration, but a clear role in striatal neurophysiology and animal behavior has emerged. Alterations in LRRK2 impair dopamine (DA) transmission, regulation and signaling, in addition to corticostriatal synaptic plasticity...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28195154/zinc-finger-protein-zpr9-functions-as-an-activator-of-ampk-related-serine-threonine-kinase-mpk38-melk-involved-in-ask1-tgf-%C3%AE-p53-signaling-pathways
#5
Hyun-A Seong, Ravi Manoharan, Hyunjung Ha
Murine protein serine-threonine kinase 38 (MPK38), an AMP-activated protein kinase (AMPK)-related kinase, has been implicated in the induction of apoptosis signal-regulating kinase 1 (ASK1)-, transforming growth factor-β (TGF-β)-, and p53-mediated activity involved in metabolic homeostasis. Here, zinc finger protein ZPR9 was found to be an activator of MPK38. The association of MPK38 and ZPR9 was mediated by cysteine residues present in each of these two proteins, Cys(269) and Cys(286) of MPK38 and Cys(305) and Cys(308) of ZPR9...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28194446/knockin-mouse-with-mutant-g%C3%AE-11-mimics-human-inherited-hypocalcemia-and-is-rescued-by-pharmacologic-inhibitors
#6
Kelly L Roszko, Ruiye Bi, Caroline M Gorvin, Hans Bräuner-Osborne, Xiao-Feng Xiong, Asuka Inoue, Rajesh V Thakker, Kristian Strømgaard, Thomas Gardella, Michael Mannstadt
Heterotrimeric G proteins play critical roles in transducing extracellular signals generated by 7-transmembrane domain receptors. Somatic gain-of-function mutations in G protein α subunits are associated with a variety of diseases. Recently, we identified gain-of-function mutations in Gα11 in patients with autosomal-dominant hypocalcemia type 2 (ADH2), an inherited disorder of hypocalcemia, low parathyroid hormone (PTH), and hyperphosphatemia. We have generated knockin mice harboring the point mutation GNA11 c...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28188885/trpm5-expression-in-the-olfactory-epithelium
#7
Martina Pyrski, Eugenia Eckstein, Andreas Schmid, Bernd Bufe, Jan Weiss, Vladimir Chubanov, Ulrich Boehm, Frank Zufall
The Ca(2+)-activated monovalent cation channel Trpm5 is a key element in chemotransduction of taste receptor cells of the tongue, but the extent to which Trpm5 channels are expressed in olfactory sensory neurons (OSNs) of the main olfactory epithelium (MOE) of adult mice as part of a specific pheromonal detection system is debated. Here, we used a novel Trpm5-IRES-Cre knockin strain to drive Cre recombinase expression, employed previously validated Trpm5 antibodies, performed in situ hybridization experiments to localize Trpm5 RNA, and searched extensively for Trpm5 splice variants in genetically-labeled, Trpm5-expressing MOE cells...
February 7, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28143571/single-cas9-nickase-induced-generation-of-nramp1-knockin-cattle-with-reduced-off-target-effects
#8
Yuanpeng Gao, Haibo Wu, Yongsheng Wang, Xin Liu, Linlin Chen, Qian Li, Chenchen Cui, Xu Liu, Jingcheng Zhang, Yong Zhang
BACKGROUND: The CRISPR-Cas9 system is a widely utilized platform for transgenic animal production in various species, although its off-target effects should be addressed. Several applications of this tool have been proposed in model animals but remain insufficient for transgenic livestock production. RESULTS: Here, we report the first application of single Cas9 nickase (Cas9n) to induce gene insertion at a selected locus in cattle. We identify the main binding sites of a catalytically inactive Cas9 (dCas9) protein in bovine fetal fibroblast cells (BFFs) with chromatin immunoprecipitation sequencing (ChIP-seq)...
February 1, 2017: Genome Biology
https://www.readbyqxmd.com/read/28137876/sirtuin1-regulated-lysine-acetylation-of-p66shc-governs-diabetes-induced-vascular-oxidative-stress-and-endothelial-dysfunction
#9
Santosh Kumar, Young-Rae Kim, Ajit Vikram, Asma Naqvi, Qiuxia Li, Modar Kassan, Vikas Kumar, Markus M Bachschmid, Julia S Jacobs, Ajay Kumar, Kaikobad Irani
The 66-kDa Src homology 2 domain-containing protein (p66Shc) is a master regulator of reactive oxygen species (ROS). It is expressed in many tissues where it contributes to organ dysfunction by promoting oxidative stress. In the vasculature, p66Shc-induced ROS engenders endothelial dysfunction. Here we show that p66Shc is a direct target of the Sirtuin1 lysine deacetylase (Sirt1), and Sirt1-regulated acetylation of p66Shc governs its capacity to induce ROS. Using diabetes as an oxidative stimulus, we demonstrate that p66Shc is acetylated under high glucose conditions and is deacetylated by Sirt1 on lysine 81...
January 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28137869/akt-signaling-is-critical-for-memory-cd8-t-cell-development-and-tumor-immune-surveillance
#10
Anne Rogel, Jane E Willoughby, Sarah L Buchan, Henry J Leonard, Stephen M Thirdborough, Aymen Al-Shamkhani
Memory CD8(+) T cells confer long-term immunity against tumors, and anticancer vaccines therefore should maximize their generation. Multiple memory CD8(+) T-cell subsets with distinct functional and homing characteristics exist, but the signaling pathways that regulate their development are ill defined. Here we examined the role of the serine/threonine kinase Akt in the generation of protective immunity by CD8(+) T cells. Akt is known to be activated by the T-cell antigen receptor and the cytokine IL-2, but its role in T-cell immunity in vivo has not been explored...
February 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28133799/human-ig-knockin-mice-to-study-the-development-and-regulation-of-hiv-1-broadly-neutralizing-antibodies
#11
REVIEW
Laurent Verkoczy, Frederick W Alt, Ming Tian
A major challenge for HIV-1 vaccine research is developing a successful immunization approach for inducing broadly neutralizing antibodies (bnAbs). A key shortcoming in meeting this challenge has been the lack of animal models capable of identifying impediments limiting bnAb induction and ranking vaccine strategies for their ability to promote bnAb development. Since 2010, immunoglobulin knockin (KI) technology, involving inserting functional rearranged human variable exons into the mouse IgH and IgL loci has been used to express bnAbs in mice...
January 2017: Immunological Reviews
https://www.readbyqxmd.com/read/28130172/brain-specific-knockin-of-the-pathogenic-tubb5-e401k-allele-causes-defects-in-motor-coordination-and-prepulse-inhibition
#12
Martin W Breuss, Andi H Hansen, Lukas Landler, David A Keays
The generation, migration, and differentiation of neurons requires the functional integrity of the microtubule cytoskeleton. Mutations in the tubulin gene family are known to cause various neurological diseases including lissencephaly, ocular motor disorders, polymicrogyria and amyotrophic lateral sclerosis. We have previously reported that mutations in TUBB5 cause microcephaly that is accompanied by severe intellectual impairment and motor delay. Here we present the characterization of a Tubb5 mouse model that allows for the conditional expression of the pathogenic E401K mutation...
January 25, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28122244/distinct-brca1-mutations-differentially-reduce-hematopoietic-stem-cell-function
#13
Victoria E Mgbemena, Robert A J Signer, Ranjula Wijayatunge, Travis Laxson, Sean J Morrison, Theodora S Ross
BRCA1 is a well-known DNA repair pathway component and a tissue-specific tumor suppressor. However, its role in hematopoiesis is uncertain. Here, we report that a cohort of patients heterozygous for BRCA1 mutations experienced more hematopoietic toxicity from chemotherapy than those with BRCA2 mutations. To test whether this reflects a requirement for BRCA1 in hematopoiesis, we generated mice with Brca1 mutations in hematopoietic cells. Mice homozygous for a null Brca1 mutation in the embryonic hematopoietic system (Vav1-iCre;Brca1(F22-24/F22-24)) developed hematopoietic defects in early adulthood that included reduced hematopoietic stem cells (HSCs)...
January 24, 2017: Cell Reports
https://www.readbyqxmd.com/read/28119464/ser1928-phosphorylation-by-pka-stimulates-the-l-type-ca2-channel-cav1-2-and-vasoconstriction-during-acute-hyperglycemia-and-diabetes
#14
Matthew A Nystoriak, Madeline Nieves-Cintrón, Tommaso Patriarchi, Olivia R Buonarati, Maria Paz Prada, Stefano Morotti, Eleonora Grandi, Julia Dos Santos Fernandes, Katherine Forbush, Franz Hofmann, Kent C Sasse, John D Scott, Sean M Ward, Johannes W Hell, Manuel F Navedo
Hypercontractility of arterial myocytes and enhanced vascular tone during diabetes are, in part, attributed to the effects of increased glucose (hyperglycemia) on L-type CaV1.2 channels. In murine arterial myocytes, kinase-dependent mechanisms mediate the increase in CaV1.2 activity in response to increased extracellular glucose. We identified a subpopulation of the CaV1.2 channel pore-forming subunit (α1C) within nanometer proximity of protein kinase A (PKA) at the sarcolemma of murine and human arterial myocytes...
January 24, 2017: Science Signaling
https://www.readbyqxmd.com/read/28116477/regulation-and-function-of-mecp2-ser421-phosphorylation-in-u50488-induced-conditioned-place-aversion-in-mice
#15
Anthony S Zannas, Jun H Kim, Anne E West
RATIONALE: Phosphorylation of the methyl DNA-binding protein MeCP2 at Ser421 (pMeCP2-S421) is induced in corticolimbic brain regions during exposure to drugs of abuse and modulates reward-driven behaviors. However, whether pMeCP2-S421 is also involved in behavioral adaptations to aversive drugs is unknown. OBJECTIVES: Our goal was to establish the role and regulation of pMeCP2-S421 in corticolimbic brain regions of mice upon acute treatment with the kappa opioid receptor agonist U50488 and during the expression of U50488-induced conditioned place aversion (CPA)...
January 23, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28098219/combined-lrrk2-mutation-aging-and-chronic-low-dose-oral-rotenone-as-a-model-of-parkinson-s-disease
#16
Hui-Fang Liu, Philip Wing-Lok Ho, Gideon Chi-Ting Leung, Colin Siu-Chi Lam, Shirley Yin-Yu Pang, Lingfei Li, Michelle Hiu-Wai Kung, David Boyer Ramsden, Shu-Leong Ho
Aging, genetics and environmental toxicity are important etiological factors in Parkinson's disease (PD). However, its pathogenesis remains unclear. A major obstacle is the lack of an appropriate experimental model which incorporates genetic susceptibility, aging and prolonged environmental toxicity. Here, we explored the interplay amongst these factors using mutant LRRK2(R1441G) (leucine-rich-repeat-kinase-2) knockin mice. We found that mutant primary cortical and mesencephalic dopaminergic neurons were more susceptible to rotenone-induced ATP deficiency and cell death...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28097237/oxidized-camkii-promotes-asthma-through-the-activation-of-mast-cells
#17
Jingjing Qu, Danh C Do, Yufeng Zhou, Elizabeth Luczak, Wayne Mitzner, Mark E Anderson, Peisong Gao
Oxidation of calmodulin-dependent protein kinase II (ox-CaMKII) by ROS has been associated with asthma. However, the contribution of ox-CaMKII to the development of asthma remains to be fully characterized. Here, we tested the effect of ox-CaMKII on IgE-mediated mast cell activation in an allergen-induced mouse model of asthma using oxidant-resistant CaMKII MMVVδ knockin (MMVVδ) mice. Compared with WT mice, the allergen-challenged MMVVδ mice displayed less airway hyperresponsiveness (AHR) and inflammation...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28096221/efficient-crispr-cas9-assisted-gene-targeting-enables-rapid-and-precise-genetic-manipulation-of-mammalian-neural-stem-cells
#18
Raul Bardini Bressan, Pooran Singh Dewari, Maria Kalantzaki, Ester Gangoso, Mantas Matjusaitis, Claudia Garcia-Diaz, Carla Blin, Vivien Grant, Harry Bulstrode, Sabine Gogolok, William C Skarnes, Steven M Pollard
Mammalian neural stem (NS) cell lines provide a tractable model for discovery across stem cell and developmental biology, regenerative medicine and neuroscience. They can be derived from foetal or adult germinal tissues and continuously propagated in vitro as adherent monolayers. NS cells are clonally expandable, genetically stable, and easily transfectable - experimental attributes compatible with targeted genetic manipulations. However, gene targeting - so critical for functional studies of embryonic stem cells - has not been exploited to date in NS cells...
January 17, 2017: Development
https://www.readbyqxmd.com/read/28094771/orphan-gpr182-suppresses-erk-mediated-intestinal-proliferation-during-regeneration-and-adenoma-formation
#19
Daniel O Kechele, R Eric Blue, Bailey Zwarycz, Scott T Espenschied, Amanda T Mah, Marni B Siegel, Charles M Perou, Shengli Ding, Scott T Magness, P Kay Lund, Kathleen M Caron
Orphan GPCRs provide an opportunity to identify potential pharmacological targets, yet their expression patterns and physiological functions remain challenging to elucidate. Here, we have used a genetically engineered knockin reporter mouse to map the expression pattern of the Gpr182 during development and adulthood. We observed that Gpr182 is expressed at the crypt base throughout the small intestine, where it is enriched in crypt base columnar stem cells, one of the most active stem cell populations in the body...
February 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28053051/rom1-converts-y141c-prph2-associated-pattern-dystrophy-to-retinitis-pigmentosa
#20
Shannon M Conley, Michael W Stuck, Jamie N Watson, Muna I Naash
Mutations in peripherin 2 (PRPH2), also known as retinal degeneration slow/RDS, lead to various retinal degenerations including retinitis pigmentosa (RP) and macular/pattern dystrophy (MD/PD). PRPH2-associated disease is often characterized by a phenotypic variability even within families carrying the same mutation, raising interest in potential modifiers. PRPH2 oligomerizes with its homologue rod outer segment (OS) membrane protein 1 (ROM1), and non-pathogenic PRPH2/ROM1 mutations, when present together, lead to digenic RP...
January 4, 2017: Human Molecular Genetics
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