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Knock in mice

Astrid Hagelkruys, Mirjam A Moser, Christian Seiser
Histone deacetylases (HDACs) play crucial roles during mammalian development and for cellular homeostasis. In addition, these enzymes are promising targets for small molecule inhibitors in the treatment of cancer and neurological diseases. Conditional HDAC knock-out mice are excellent tools for defining the functions of individual HDACs in vivo and for identifying the molecular targets of HDAC inhibitors in disease. Here, we describe the generation of tissue-specific HDAC knock-out mice and delineate a strategy for the generation of conditional HDAC knock-in mice...
2017: Methods in Molecular Biology
Olena Bukalo, Philip R Lee, R Douglas Fields
Action-potential-induced LTD (AP-LTD) is a form of synaptic plasticity that reduces synaptic strength in CA1 hippocampal neurons firing antidromically during sharp-wave ripples. This firing occurs during slow-wave sleep and quiet moments of wakefulness, which are periods of offline replay of neural sequences learned during encoding sensory information. Here we report that rapid and persistent down-regulation of different mRNA transcripts of the BDNF gene accompanies AP-LTD, and that AP-LTD is abolished in mice with the BDNF gene knocked out in CA1 hippocampal neurons...
October 16, 2016: Neuroscience Letters
Jimena Giudice, Zheng Xia, Wei Li, Thomas A Cooper
The RNA binding protein Celf1 regulates alternative splicing in the nucleus and mRNA stability and translation in the cytoplasm. Celf1 is strongly down-regulated during mouse postnatal heart development. Its re-induction in adults induced severe heart failure and reversion to fetal splicing and gene expression patterns. However, the impact of Celf1 depletion on cardiac transcriptional and posttranscriptional dynamics in neonates has not been addressed. We found that homozygous Celf1 knock-out neonates exhibited cardiac dysfunction not observed in older homozygous animals, although homozygous mice are smaller than wild type littermates throughout development...
October 19, 2016: Scientific Reports
Amel Dudakovic, Emily T Camilleri, Scott M Riester, Christopher R Paradise, Martina Gluscevic, Thomas M O'Toole, Roman Thaler, Jared M Evans, Huihuang Yan, Malayannan Subramaniam, John R Hawse, Gary S Stein, Martin A Montecino, Meghan E McGee-Lawrence, Jennifer J Westendorf, Andre J van Wijnen
Perturbations in skeletal development and bone degeneration may result in reduced bone mass and quality leading to greater fracture risk. Bone loss is mitigated by bone protective therapies, but there is a clinical need for new bone-anabolic agents. Previous work has demonstrated that enhancer of zeste homolog 2 (Ezh2), a histone 3 lysine 27 (H3K27) methyltransferase, suppressed differentiation of osteogenic progenitors. Here, we investigated if inhibition of Ezh2 can be leveraged for bone stimulatory applications...
October 10, 2016: Journal of Biological Chemistry
Carl B Gillombardo, Rebecca Darrah, Thomas E Dick, Michael Moore, Nathan Kong, Michael J Decker, Fang Han, Motoo Yamauchi, Mathias Dutschmann, Sausan Azzam, Kingman P Strohl
RATIONALE: Brainstem apolipoprotein AII (apoa2) mRNA expression correlates with apnea in breathing present in the adult C57Bl/6J (B6) sleep apnea model. OBJECTIVES: To test the hypothesis that the B6 apoa2 gene contributes to the trait, we performed plethysmographic testing in apoa2 knock out (KO: -/-) mice, an in situ brainstem-spinal cord preparation comparing KO to WT (+/+) mice, and B6xDBA recombinant inbred strains (RISs). MEASUREMENTS AND MAIN RESULTS: Apoa2 WT do, but KO and heterozygote (+/-) mice do not exhibit apnea during post-hypoxic breathing, measured in vivo...
October 15, 2016: Respiratory Physiology & Neurobiology
Wen-Juan Gan, Jing-Ru Wang, Xiao-Li Zhu, Xiao-Shun He, Peng-Da Guo, Shen Zhang, Xiu-Ming Li, Jian-Ming Li, Hua Wu
BACKGROUND: Aberrant expression of Retinoic acid receptor γ (RARγ) is implicated in cancer development. Our previous study identified that RARγ functions as a tumor promoter to drive hepatocellular carcinoma (HCC) growth. However, its contribution to HCC invasion and metastasis remains unclear. METHODS: RARγ expression in clinical HCC samples was detected by western blot and immunohistochemistry. The relationship between RARγ expression levels and the clinical characteristics were evaluated...
October 19, 2016: Journal of Experimental & Clinical Cancer Research: CR
Jin-Jer Chen, Wen-Rui Hao, Kuan-Cheng Chang, Ju-Chi Liu
OBJECTIVE: Cardiac fibrosis is the major pathophysiological process, contributing to the development of diastolic heart failure. We examine the role of macrophage-derived galectin-3 (gal-3) in cardiac fibrosis and diastolic function in response to transverse aortic constriction (TAC). DESIGN AND METHOD: wild-type (WT) and gal-3 knock-out (KO) mice subjected to TAC; immunohistochemistry for myocardial macrophage infiltration,gal-3,and CTGF (connective tissue growth factor) expression; picrosirius red stain for myocardial fibrosis; FACS flow- cytometry for defining the origin of myocardial macrophages...
September 2016: Journal of Hypertension
Fei Yu, Hui Zeng, Ming Lei, De-Ming Xiao, Wei Li, Hao Yuan, Jian-Jing Lin
This study investigated the effects of SIRT1 gene knock-out on osteoarthritis in mice, and the possible roles of SREBP2 protein and the PI3K/AKT signaling pathway in the effects. Mice were randomly divided into a normal group and a SIRT1 gene knock-out group (6 mice in each group). In these groups, one side of the knee anterior cruciate ligament was traversed, and the ipsilateral medial meniscus was cut to establish an osteoarthritis model of knee joint. The countralateral synovial bursa was cut out, serving as controls...
October 2016: Journal of Huazhong University of Science and Technology. Medical Sciences
Christian Brigolin, Nathan McKenty, Kirit Pindolia, Barry Wolf
Biotinidase deficiency is an autosomal recessively inherited disorder characterized by neurological and cutaneous abnormalities. Untreated individuals with biotinidase deficiency cannot recycle biotin from biocytin (N-biotinyl-ϵ-lysine), the proteolytic digestion product of protein-bound biotin. Biotin therapy can markedly resolve symptoms, or can prevent the development of symptoms if initiated early. To understand better the pathogenesis of the neurological problems in the disorder in humans, we have compared gene transcription changes during the first week post-birth in the brains of biotinidase-deficient, transgenic, knock-out mice at days 1 and 8 and compared to changes in wildtype mice at the same times...
December 2016: Molecular Genetics and Metabolism Reports
Christopher S Medina, Octavian Biris, Tomas L Falzone, Xiaowei Zhang, Amber J Zimmerman, Elaine L Bearer
Microtubule-based motors carry cargo back and forth between the synaptic region and the cell body. Defects in axonal transport result in peripheral neuropathies, some of which are caused by mutations in KIF5A, a gene encoding one of the heavy chain isoforms of conventional kinesin-1. Some mutations in KIF5A also cause severe central nervous system defects in humans. While transport dynamics in the peripheral nervous system have been well characterized experimentally, transport in the central nervous system is less experimentally accessible and until now not well described...
October 14, 2016: NeuroImage
Michael Rehman, Sreeharsha Gurrapu, Gabriella Cagnoni, Lorena Capparuccia, Luca Tamagnone
The secreted semaphorin Sema3E controls cell migration and invasiveness in cancer cells. Sema3E-receptor, PlexinD1, is frequently upregulated in melanoma, breast, colon, ovarian and prostate cancers; however, the mechanisms underlying PlexinD1 upregulation and the downstream events elicited in tumor cells are still unclear. Here we show that the canonical RBPjk-dependent Notch signaling cascade controls PlexinD1 expression in primary endothelial and cancer cells. Transcriptional activation was studied by quantitative PCR and promoter activity reporter assays...
2016: PloS One
Shouta Sugio, Koujiro Tohyama, Shinichiro Oku, Kanehiro Fujiyoshi, Takeshi Yoshimura, Keigo Hikishima, Ryutaro Yano, Takahiro Fukuda, Masaya Nakamura, Hideyuki Okano, Masahiko Watanabe, Masaki Fukata, Kazuhiro Ikenaka, Kenji F Tanaka
Astrocytes have recently been shown to provide physiological support for various brain functions, although little is known about their involvement in white matter integrity. Several inherited infantile-onset leukoencephalopathies, such as Alexander disease and megalencephalic leukoencephalopathy with subcortical cysts (MLC), implicate astrocytic involvement in the formation of white matter. Several mouse models of MLC had been generated by knocking out the Mlc1 gene; however, none of those models was reported to show myelin abnormalities prior to formation of the myelin sheath...
October 17, 2016: Glia
Miguel A Gonzalez-Lozano, Patricia Klemmer, Titia Gebuis, Chopie Hassan, Pim van Nierop, Ronald E van Kesteren, August B Smit, Ka Wan Li
Development of the brain involves the formation and maturation of numerous synapses. This process requires prominent changes of the synaptic proteome and potentially involves thousands of different proteins at every synapse. To date the proteome analysis of synapse development has been studied sparsely. Here, we analyzed the cortical synaptic membrane proteome of juvenile postnatal days 9 (P9), P15, P21, P27, adolescent (P35) and different adult ages P70, P140 and P280 of C57Bl6/J mice. Using a quantitative proteomics workflow we quantified 1560 proteins of which 696 showed statistically significant differences over time...
October 17, 2016: Scientific Reports
Anna Ngo, Ann Koay, Christian Pecquet, Carmen C Diaconu, Yasmine Ould-Amer, Qiwei Huang, Congbao Kang, Anders Poulsen, May Ann Lee, David Jenkins, Andrew Shiau, Stefan N Constantinescu, Meng Ling Choo
BACKGROUND: Rather than a Janus Kinase 2 inhibitor (ruxolitinib), a specific thrombopoietin receptor (TpoR) inhibitor would be more specific for the treatment of myeloproliferative neoplasms due to TpoR mutations. OBJECTIVE: A cell-based phenotypic approach to identify specific TpoR inhibitors was implemented and a library of 505,483 small molecules was screened for inhibitory effects on cells transformed by TpoR mutants. RESULTS: Among the identified hits are two analogs of 3-(4-piperidinyl) indole...
October 10, 2016: Combinatorial Chemistry & High Throughput Screening
Ragnhild Reehorst Lereim, Eystein Oveland, Yichuan Xiao, Øivind Torkildsen, Stig Wergeland, Kjell-Morten Myhr, Shao-Cong Sun, Frode S Berven
The ubiquitin ligase Peli1 has previously been suggested as a potential treatment target in multiple sclerosis. In the multiple sclerosis disease model, experimental autoimmune encephalomyelitis, Peli1 knock-out led to less activated microglia and less inflammation in the central nervous system. Despite being important in microglia, Peli1 expression has also been detected in glial and neuronal cells. In the present study the overall brain proteomes of Peli1 knock-out mice and wild-type mice were compared prior to experimental autoimmune encephalomyelitis induction, at onset of the disease and at disease peak...
September 2016: Journal of Proteomics & Bioinformatics
Imranul Alam, Amie K McQueen, Dena Acton, Austin M Reilly, Rita L Gerard-O'Riley, Dana K Oakes, Charishma Kasipathi, Abigail Huffer, Weston B Wright, Michael J Econs
Autosomal dominant osteopetrosis type II (ADO2) is a heritable osteosclerotic bone disorder due to dysfunctional osteoclast activity. ADO2 is caused by missense mutations in the chloride channel 7 (CLCN7) gene characterized by osteosclerosis with multiple fractures. ADO2 can result in osteomyelitis, visual loss and bone marrow failure. Currently, there is no cure for ADO2, and until recently no appropriate animal model of ADO2 existed to understand better the pathogenesis of this disease and to test new therapies...
October 13, 2016: Bone
Takahito Nakama, Shigeo Yoshida, Keijiro Ishikawa, Yoshiyuki Kobayashi, Takaya Abe, Hiroshi Kiyonari, Go Shioi, Naruto Katsuragi, Tatsuro Ishibashi, Ryuichi Morishita, Yoshiaki Taniyama
Retinal neovascularization (NV) due to retinal ischemia is one of the major causes of vision reduction in patients with different types of retinal diseases although anti-vascular endothelial growth factor (anti-VEGF) therapy can partially reduce the size of the retinal NV. We recently reported that periostin plays an important role in the development of NV and the formation of preretinal fibrovascular membranes, but the role of the splice variants of periostin on retinal NV has not been determined. We examined the expressions of periostin splice variants in the ischemic retinas of a mouse model of oxygen-induced retinal NV...
October 12, 2016: Experimental Eye Research
Deeba Noreen Baig, Toru Yanagawa, Katsuhiko Tabuchi
Synaptic cell adhesion molecules (SCAMs) are a functional category of cell adhesion molecules that connect pre- and postsynapses by the protein-protein interaction via their extracellular cell adhesion domains. Countless numbers of common genetic variants and rare mutations in SCAMs have been identified in the patients with autism spectrum disorders (ASDs). Among these, NRXN and NLGN family proteins cooperatively function at synaptic terminals both of which genes are strongly implicated as risk genes for ASDs...
October 12, 2016: Brain Research Bulletin
E Sacide Çağlayan
Dual-specificity thyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a strong therapeutic target to ameliorate cognitive functions of Down Syndrome (DS). Genetic normalization of Dyrk1a is sufficient to normalize early cortical developmental phenotypes in DS mouse models. Gyrencephalic human neocortical development is more complex than that in lissencephalic mice, hence cerebral organoids (COs) can be used to model early neurodevelopmental defects of DS. Single copy DYRK1A knockout COs (scDYRK1AKO-COs) can be generated from manipulated DS derived (DS-) induced pluripotent stem cells (iPSCs) and genetic normalization of DYRK1A is expected to result in corrected neurodevelopmental phenotypes that can be reminiscent of normal COs...
October 15, 2016: Cell Biology International
Changhwan Ahn, Dongoh Lee, Jae-Hwan Lee, Hyun Yang, Beum-Soo An, Eui-Bae Jeung
It has been proposed that cellular Ca2+ signals activate hormone secretion. In pancreatic β cells, which produce insulin, Ca2+ signals have been known to contribute to insulin secretion. Prior to this study, we confirmed that insulin-secreting β cells express CaBP-9k, and assumed that CaBP-9k play a role in β cell insulin synthesis or secretion. Using CaBP-9k knock out (KO) mice, we demonstrated that ablation of CaBP-9k causes reducing insulin secretion and increasing serum glucose. To compare the role of CaBP-9k with pathophysiological conditions, we exposed wild-type and CaBP-9k KO mice to hypoxic conditions for 10 days...
2016: PloS One
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