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https://www.readbyqxmd.com/read/29449377/haploid-embryonic-stem-cells-can-be-enriched-and-maintained-by-simple-filtration
#1
Chao Qu, Meng Yan, Suming Yang, Lingbo Wang, Qi Yin, Yuan Liu, Yeguang Chen, Jinsong Li
Haploid mammalian embryonic stem cells (haESCs) serve as a powerful tool for genetic analyses at both cellular and organismal levels. However, spontaneous diploidization of haESCs limits their use in these analyses. Addition of small molecules to culture medium to control the cell cycle can slow down diploidization, but cell-sorting methods such as FACS are still required to enrich haploid cells for long-term maintenance in vitro. Here, acting on our observation that haploid and diploidized cells differ in diameter, we developed a simplified filtration method to enrich haploid cells from cultured haESCs...
February 15, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29422515/notch-signaling-regulates-hey2-expression-in-a-spatiotemporal-dependent-manner-during-cardiac-morphogenesis-and-trabecular-specification
#2
Lianjie Miao, Jingjing Li, Jun Li, Xueying Tian, Yangyang Lu, Saiyang Hu, David Shieh, Ryan Kanai, Bo-Yang Zhou, Bin Zhou, Jiandong Liu, Anthony B Firulli, James F Martin, Harold Singer, Bin Zhou, Hongbo Xin, Mingfu Wu
Hey2 gene mutations in both humans and mice have been associated with multiple cardiac defects. However, the currently reported localization of Hey2 in the ventricular compact zone cannot explain the wide variety of cardiac defects. Furthermore, it was reported that, in contrast to other organs, Notch doesn't regulate Hey2 in the heart. To determine the expression pattern and the regulation of Hey2, we used novel methods including RNAscope and a Hey2 CreERT2 knockin line to precisely determine the spatiotemporal expression pattern and level of Hey2 during cardiac development...
February 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29416084/nuclear-fak-and-its-kinase-activity-regulate-vegfr2-transcription-in-angiogenesis-of-adult-mice
#3
Shaogang Sun, Hsin-Jung Wu, Jun-Lin Guan
Focal adhesion kinase (FAK) is essential in embryonic angiogenesis by regulating endothelial cell (EC) survival and barrier functions through its kinase-independent and -dependent activities. Here, we generated EC-specific tamoxifen-inducible FAK knockout and FAK kinase-defective (KD) mutant knockin mice to investigate the role of FAK and its kinase activity in angiogenesis of adult animals. Unlike previous observations of their differential defects in embryonic vascular development, both FAK ablation and inactivation of its kinase activity resulted in deficient angiogenesis in wound-healing as well as retinal angiogenesis models...
February 7, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29386660/establishment-and-analysis-of-a-novel-mouse-line-carrying-a-conditional-knockin-allele-of-a-cancer-specific-fbxw7-mutation
#4
Tsuneo Ikenoue, Yumi Terakado, Chi Zhu, Xun Liu, Tomoyuki Ohsugi, Daisuke Matsubara, Tomoki Fujii, Shigeru Kakuta, Sachiko Kubo, Takuma Shibata, Kiyoshi Yamaguchi, Yoichiro Iwakura, Yoichi Furukawa
F-box and WD40 domain protein 7 (FBXW7) is a component of the SKP1-CUL1-F-box protein (SCF) complex that mediates the ubiquitination of diverse oncogenic target proteins. The exploration of FBXW7 mutations in human primary cancer has revealed three mutation hotspots at conserved arginine residues (Arg465, Arg479, and Arg505) in the WD40 domain, which are critical for substrate recognition. To study the function of human FBXW7 R465C , the most frequent mutation in human malignancies, we generated a novel conditional knockin mouse line of murine Fbxw7 R468C corresponding to human FBXW7 R465C ...
January 31, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29386392/robust-kinase-and-age-dependent-dopaminergic-and-norepinephrine-neurodegeneration-in-lrrk2-g2019s-transgenic-mice
#5
Yulan Xiong, Stewart Neifert, Senthilkumar S Karuppagounder, Qinfang Liu, Jeannette N Stankowski, Byoung Dae Lee, Han Seok Ko, Yunjong Lee, Jonathan C Grima, Xiaobo Mao, Haisong Jiang, Sung-Ung Kang, Deborah A Swing, Lorraine Iacovitti, Lino Tessarollo, Ted M Dawson, Valina L Dawson
Mutations in LRRK2 are known to be the most common genetic cause of sporadic and familial Parkinson's disease (PD). Multiple lines of LRRK2 transgenic or knockin mice have been developed, yet none exhibit substantial dopamine (DA)-neuron degeneration. Here we develop human tyrosine hydroxylase (TH) promoter-controlled tetracycline-sensitive LRRK2 G2019S (GS) and LRRK2 G2019S kinase-dead (GS/DA) transgenic mice and show that LRRK2 GS expression leads to an age- and kinase-dependent cell-autonomous neurodegeneration of DA and norepinephrine (NE) neurons...
January 31, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29378953/disease-causing-mutation-in-%C3%AE-actinin-4-promotes-podocyte-detachment-through-maladaptation-to-periodic-stretch
#6
Di Feng, Jacob Notbohm, Ava Benjamin, Shijie He, Minxian Wang, Lay-Hong Ang, Minaspi Bantawa, Mehdi Bouzid, Emanuela Del Gado, Ramaswamy Krishnan, Martin R Pollak
α-Actinin-4 (ACTN4) bundles and cross-links actin filaments to confer mechanical resilience to the reconstituted actin network. How this resilience is built and dynamically regulated in the podocyte, and the cause of its failure in ACTN4 mutation-associated focal segmental glomerulosclerosis (FSGS), remains poorly defined. Using primary podocytes isolated from wild-type (WT) and FSGS-causing point mutant Actn4 knockin mice, we report responses to periodic stretch. While WT cells largely maintained their F-actin cytoskeleton and contraction, mutant cells developed extensive and irrecoverable reductions in these same properties...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29364218/production-of-genetically-engineered-golden-syrian-hamsters-by-pronuclear-injection-of-the-crispr-cas9-complex
#7
Rong Li, Jinxin Miao, Zhiqiang Fan, SeokHwan Song, Il-Keun Kong, Yaohe Wang, Zhongde Wang
The pronuclear (PN) injection technique was first established in mice to introduce foreign genetic materials into the pronuclei of one-cell stage embryos. The introduced genetic material may integrate into the embryonic genome and generate transgenic animals with foreign genetic information following transfer of the injected embryos to foster mothers. Following the success in mice, PN injection has been applied successfully in many other animal species. Recently, PN injection has been successfully employed to introduce reagents with gene-modifying activities, such as the CRISPR/Cas9 system, to achieve site-specific genetic modifications in several laboratory and farm animal species...
January 9, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29361670/podocyte-specific-knockin-of-pten-protects-kidney-from-hyperglycemia
#8
Huizhen Wang, Ziwei Feng, Jianteng Xie, Feng Wen, Menglei Jv, Tiantian Liang, Jing Li, Yanhui Wang, Yangyang Zuo, Sheng Li, Ruizhao Li, Zhilian Li, Bin Zhang, Xinling Liang, Shuangxin Liu, Wei Shi, Wenjian Wang
Aim Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has been proved to be downregulated in podocytes challenged with high glucose (HG), and knockout of PTEN in podocytes aggravated the progression of diabetic kidney disease (DKD). However, whether podocyte-specific knockin of PTEN protects the kidney against hyperglycemia in vivo remains undefined. Methods The inducible podocyte-specific PTEN knockin (PPKI) mice were generated by crossing newly created transgenic loxP-stop-loxP-PTEN mice with podocin-iCreERT2 mice...
January 17, 2018: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29360942/il-6-trans-activation-contributes-to-aldosterone-induced-cardiac-fibrosis
#9
Chia-Hung Chou, Chi-Sheng Hung, Che-Wei Liao, Lin-Hung Wei, Ching-Way Chen, Chia-Tung Shun, Wen-Fen Wen, Cho-Hua Wan, Xue-Ming Wu, Yi-Yao Chang, Vin-Cent Wu, Kwan-Dun Wu, Yen-Hung Lin
Aims: An excess of aldosterone results in cardiac remodeling and fibrosis. Interleukin-6 (IL-6) is a key mediator in the fibrotic process, however the effect of aldosterone on the expression of IL-6 remains unclear. We investigated whether aldosterone induces the expression of IL-6 and thereby contributes to the fibrotic process. Methods and Results: In this clinical study, we prospectively enrolled 25 patients with primary aldosteronism (PA) and 26 patients with essential hypertension (EH)...
January 19, 2018: Cardiovascular Research
https://www.readbyqxmd.com/read/29353819/interference-with-the-c-terminal-structure-of-marf1-causes-defective-oocyte-meiotic-division-and-female-infertility-in-mice
#10
Guang-Yi Cao, Ming-Zhe Li, Hao Wang, Lan-Ying Shi, You-Qiang Su
Meiosis-arrest female 1 (MARF1) is a recently identified key oogenic regulator essential for the maintenance of female fertility and genome integrity in mice. However, the detailed functions and the underlying mechanisms of MARF1 remain elusive. Here, in an attempt to create a mouse model expressing fluorescent protein-tagged MARF1 to facilitate further exploration of the roles of MARF1 in oocytes, we produced a Marf1-eGFP knockin (KI) mouse line in which the C-terminal structure and function of MARF1 were interfered by its fusing eGFP peptide...
January 18, 2018: Journal of Biomedical Research
https://www.readbyqxmd.com/read/29327727/generation-of-a-precise-oct4-hrgfp-knockin-cynomolgus-monkey-model-via-crispr-cas9-assisted-homologous-recombination
#11
Yiqiang Cui, Yuyu Niu, Jiankui Zhou, Yongchang Chen, Yiwei Cheng, Shangang Li, Zongyong Ai, Chu Chu, Hong Wang, Bo Zheng, Xuejin Chen, Jiahao Sha, Xuejiang Guo, Xingxu Huang, Weizhi Ji
No abstract text is available yet for this article.
January 12, 2018: Cell Research
https://www.readbyqxmd.com/read/29321651/auditory-neural-activity-in-congenitally-deaf-mice-induced-by-infrared-neural-stimulation
#12
Xiaodong Tan, Israt Jahan, Yingyue Xu, Stuart Stock, Changyow Claire Kwan, Carmen Soriano, Xianghui Xiao, Jaime García-Añoveros, Bernd Fritzsch, Claus-Peter Richter
To determine whether responses during infrared neural stimulation (INS) result from the direct interaction with spiral ganglion neurons (SGNs), we tested three genetically modified deaf mouse models: Atoh1-cre; Atoh1 f/f (Atoh1 conditional knockout, CKO), Atoh1-cre; Atoh1 f/kiNeurog1 (Neurog1 knockin, KI), and the Vglut3 knockout (Vglut3 -/-) mice. All animals were exposed to tone bursts and clicks up to 107 dB (re 20 µPa) and to INS, delivered with a 200 µm optical fiber. The wavelength (λ) was 1860 nm, the radiant energy (Q) 0-800 µJ/pulse, and the pulse width (PW) 100-500 µs...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29321583/allele-specific-repression-of-sox2-through-the-long-non-coding-rna-sox2ot
#13
Tobias C Messemaker, Selina M van Leeuwen, Patrick R van den Berg, Anke E J 't Jong, Robert-Jan Palstra, Rob C Hoeben, Stefan Semrau, Harald M M Mikkers
The transcription factor Sox2 controls the fate of pluripotent stem cells and neural stem cells. This gatekeeper function requires well-regulated Sox2 levels. We postulated that Sox2 regulation is partially controlled by the Sox2 overlapping long non-coding RNA (lncRNA) gene Sox2ot. Here we show that the RNA levels of Sox2ot and Sox2 are inversely correlated during neural differentiation of mouse embryonic stem cells (ESCs). Through allele-specific enhanced transcription of Sox2ot in mouse Sox2eGFP knockin ESCs we demonstrate that increased Sox2ot transcriptional activity reduces Sox2 RNA levels in an allele-specific manner...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29320730/esrrb-complementation-rescues-development-of-nanog-null-germ-cells
#14
Man Zhang, Harry G Leitch, Walfred W C Tang, Nicola Festuccia, Elisa Hall-Ponsele, Jennifer Nichols, M Azim Surani, Austin Smith, Ian Chambers
The transcription factors (TFs) Nanog and Esrrb play important roles in embryonic stem cells (ESCs) and during primordial germ-cell (PGC) development. Esrrb is a positively regulated direct target of NANOG in ESCs that can substitute qualitatively for Nanog function in ESCs. Whether this functional substitution extends to the germline is unknown. Here, we show that germline deletion of Nanog reduces PGC numbers 5-fold at midgestation. Despite this quantitative depletion, Nanog-null PGCs can complete germline development in contrast to previous findings...
January 9, 2018: Cell Reports
https://www.readbyqxmd.com/read/29298895/endoplasmic-reticulum-stress-responses-in-mouse-models-of-alzheimer-disease-overexpression-paradigm-versus-knock-in-paradigm
#15
Shoko Hashimoto, Ayano Ishii, Naoko Kamano, Naoto Watamura, Takashi Saito, Toshio Oshima, Makoto Yokosuka, Takaomi C Saido
Endoplasmic reticulum (ER) stress is believed to play an important role in the etiology of Alzheimer disease (AD). The accumulation of misfolded proteins and perturbation of intracellular calcium homeostasis are thought to underlie the induction of ER stress, resulting in neuronal dysfunction and cell death. Several reports have shown an increased ER stress response in amyloid precursor protein (APP) and presenilin1 (PS1) double transgenic (Tg) AD mouse models. However, it remains unclear whether the ER stress observed in these mouse models is actually caused by AD pathology...
January 3, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29290616/reconstruction-of-the-human-colon-epithelium-in%C3%A2-vivo
#16
Shinya Sugimoto, Yuki Ohta, Masayuki Fujii, Mami Matano, Mariko Shimokawa, Kosaku Nanki, Shoichi Date, Shingo Nishikori, Yoshihiro Nakazato, Tetsuya Nakamura, Takanori Kanai, Toshiro Sato
Genetic lineage tracing has revealed that Lgr5+ murine colon stem cells (CoSCs) rapidly proliferate at the crypt bottom. However, the spatiotemporal dynamics of human CoSCs in vivo have remained experimentally intractable. Here we established an orthotopic xenograft system for normal human colon organoids, enabling stable reconstruction of the human colon epithelium in vivo. Xenografted organoids were prone to displacement by the remaining murine crypts, and this could be overcome by complete removal of the mouse epithelium...
December 21, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/29289717/exploring-the-interaction-between-eif2%C3%AE-dysregulation-acute-endoplasmic-reticulum-stress-and-dyt1-dystonia-in-the-mammalian-brain
#17
Genevieve Beauvais, Noela Rodriguez-Losada, Lei Ying, Zuchra Zakirova, Jaime L Watson, Ben Readhead, Paul Gadue, Deborah L French, Michelle E Ehrlich, Pedro Gonzalez-Alegre
DYT1 dystonia is a neurological disease caused by dominant mutations in the TOR1A gene, encoding for the endoplasmic reticulum (ER)-resident protein torsinA. Recent reports linked expression of the DYT1-causing protein with dysregulation of eIF2α, a key component of the cellular response to ER stress known as the unfolded protein response (UPR). However, the response of the DYT1 mammalian brain to acute ER stress inducers has not been evaluated in vivo. We hypothesized that torsinA regulates the neuronal UPR and expression of its mutant form would alter this process...
December 28, 2017: Neuroscience
https://www.readbyqxmd.com/read/29281818/vaccine-induction-of-heterologous-tier-2-hiv-1-neutralizing-antibodies-in-animal-models
#18
Kevin O Saunders, Laurent K Verkoczy, Chuancang Jiang, Jinsong Zhang, Robert Parks, Haiyan Chen, Max Housman, Hilary Bouton-Verville, Xiaoying Shen, Ashley M Trama, Richard Scearce, Laura Sutherland, Sampa Santra, Amanda Newman, Amanda Eaton, Kai Xu, Ivelin S Georgiev, M Gordon Joyce, Georgia D Tomaras, Mattia Bonsignori, Steven G Reed, Andres Salazar, John R Mascola, M Anthony Moody, Derek W Cain, Mireille Centlivre, Sandra Zurawski, Gerard Zurawski, Harold P Erickson, Peter D Kwong, S Munir Alam, Yves Levy, David C Montefiori, Barton F Haynes
The events required for the induction of broad neutralizing antibodies (bnAbs) following HIV-1 envelope (Env) vaccination are unknown, and their induction in animal models as proof of concept would be critical. Here, we describe the induction of plasma antibodies capable of neutralizing heterologous primary (tier 2) HIV-1 strains in one macaque and two rabbits. Env immunogens were designed to induce CD4 binding site (CD4bs) bnAbs, but surprisingly, the macaque developed V1V2-glycan bnAbs. Env immunization of CD4bs bnAb heavy chain rearrangement (VHDJH) knockin mice similarly induced V1V2-glycan neutralizing antibodies (nAbs), wherein the human CD4bs VH chains were replaced with mouse rearrangements bearing diversity region (D)-D fusions, creating antibodies with long, tyrosine-rich HCDR3s...
December 26, 2017: Cell Reports
https://www.readbyqxmd.com/read/29262331/the-lxcxe-retinoblastoma-protein-binding-motif-of-fog-2-regulates-adipogenesis
#19
Olivier Goupille, Tipparat Penglong, Zahra Kadri, Marine Granger-Locatelli, Raphaël Denis, Serge Luquet, Cécile Badoual, Suthat Fucharoen, Leila Maouche-Chrétien, Philippe Leboulch, Stany Chrétien
GATA transcription factors and their FOG cofactors play a key role in tissue-specific development and differentiation, from worms to humans. Mammals have six GATA and two FOG factors. We recently demonstrated that interactions between retinoblastoma protein (pRb) and GATA-1 are crucial for erythroid proliferation and differentiation. We show here that the LXCXE pRb-binding site of FOG-2 is involved in adipogenesis. Unlike GATA-1, which inhibits cell division, FOG-2 promotes proliferation. Mice with a knockin of a Fog2 gene bearing a mutated LXCXE pRb-binding site are resistant to obesity and display higher rates of white-to-brown fat conversion...
December 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/29259100/mglur5-antagonism-increases-autophagy-and-prevents-disease-progression-in-the-zq175-mouse-model-of-huntington-s-disease
#20
Khaled S Abd-Elrahman, Alison Hamilton, Shaunessy R Hutchinson, Fang Liu, Ryan C Russell, Stephen S G Ferguson
Huntington's disease (HD) is a neurodegenerative disease caused by an expansion in the huntingtin protein (also called Htt) that induces neuronal cell death with age. We found that the treatment of 12-month-old symptomatic heterozygous and homozygous zQ175 huntingtin knockin mice for 12 weeks with CTEP, a negative allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), reduced the size and number of huntingtin aggregates, attenuated caspase-3 activity, and reduced both neuronal apoptosis and neuronal loss in brain tissue...
December 19, 2017: Science Signaling
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