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Genetic mouse model

J Xu, B J Hartley, P Kurup, A Phillips, A Topol, M Xu, C Ononenyi, E Foscue, S-M Ho, T D Baguley, N Carty, C S Barros, U Müller, S Gupta, P Gochman, J Rapoport, J A Ellman, C Pittenger, B Aronow, A C Nairn, M W Nestor, P J Lombroso, K J Brennand
The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1(+/-) knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1(+/-) mice...
October 18, 2016: Molecular Psychiatry
Logan Horne, Frank R Avilucea, Huifeng Jin, Jared J Barrott, Kyllie Smith-Fry, Yanliang Wang, Bang H Hoang, Kevin B Jones
Previous reports document expression of low-density lipoprotein receptor-related protein 5 (LRP5) in osteosarcoma (OS) tissue. Expression of this Wnt receptor correlated with metastatic disease and poor disease-free survival. Forced expression of dominant-negative LRP5 (dnLRP5), which lacks the membrane binding domain of the native protein and therefore functions as a soluble receptor-sponge for Wnt ligands, reduced in vitro cellular invasion and in vivo xenograft tumor growth for osteosarcoma cell lines. Here, we use a genetically engineered mouse model of osteosarcomagenesis with and without expression of dnLRP5 to assess to what degree tumorigenesis is affected and whether Wnt/β-catenin signaling is circumvented or maintained...
October 2016: Translational Oncology
Yaser Atlasi, Rubina Noori, Ivana Marolin, Patrick Franken, Joana Brandao, Katharina Biermann, Paola Collini, Mariam Grigorian, Eugene Lukanidin, Noona Ambartsumian, Riccardo Fodde
INTRODUCTION: S100a4 is a calcium-binding protein belonging to the family of S100-proteins, highly expressed in different stromal cell types. S100A4 has been reported as a prognostic marker in colorectal cancer in association with tumour progression and metastasis. METHODS: In this study, we analysed the in vivo role of S100a4 in intestinal tumour initiation and progression using different transgenic and knockout mouse models. RESULTS: We found that genetic ablation or overexpression of S100a4 in both Apc- and Smad4-mutant mice do not affect tumour initiation in the intestinal tract...
October 14, 2016: European Journal of Cancer
M Clarke, G Volpe, L Sheriff, D Walton, C Ward, W Wei, S Dumon, P García, J Frampton
Myeloproliferative neoplasms (MPN), which overproduce blood cells in the bone marrow, have recently been linked with a genetically determined decrease in expression of the MYB transcription factor. Here, we use a mouse MYB knockdown model with an MPN-like phenotype to show how lower levels of MYB lead to stem cell characteristics in myeloid progenitors. The altered progenitor properties feature elevated cytokine responsiveness, especially to IL-3, which results from increased receptor expression and increased MAPK activity leading to enhanced phosphorylation of a key regulator of protein synthesis, ribosomal protein S6...
October 17, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
John G Conboy
The Rbfox genes encode an ancient family of sequence-specific RNA binding proteins (RBPs) that are critical developmental regulators in multiple tissues including skeletal muscle, cardiac muscle, and brain. The hallmark of Rbfox proteins is a single high-affinity RRM domain, highly conserved from insects to humans, that binds preferentially to UGCAUG motifs at diverse regulatory sites in pre-mRNA introns, mRNA 3'UTRs, and pre-miRNAs hairpin structures. Versatile regulatory circuits operate on Rbfox pre-mRNA and mRNA to ensure proper expression of Rbfox1 protein isoforms, which then act on the broader transcriptome to regulate alternative splicing networks, mRNA stability and translation, and microRNA processing...
October 17, 2016: Wiley Interdisciplinary Reviews. RNA
Przemysław B Radwański, Hsiang-Ting Ho, Rengasayee Veeraraghavan, Lucia Brunello, Bin Liu, Andriy E Belevych, Sathya D Unudurthi, Michael A Makara, Silvia G Priori, Pompeo Volpe, Antonis A Armoundas, Wolfgang H Dillmann, Bjorn C Knollmann, Peter J Mohler, Thomas J Hund, Sándor Györke
BACKGROUND: Cardiac arrhythmias are a leading cause of death in the US. Vast majority of these arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with increased levels of circulating catecholamines and involve abnormal impulse formation secondary to aberrant Ca(2+) and Na(+) handling. However, the mechanistic link between β-AR stimulation and the subcellular/molecular arrhythmogenic trigger(s) remains elusive. METHODS AND RESULTS: We performed functional and structural studies to assess Ca(2+) and Na(+) signaling in ventricular myocyte as well as surface electrocardiograms in mouse models of cardiac calsequestrin (CASQ2)-associated CPVT...
June 2016: JACC. Basic to Translational Science
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
Luiz Fernando Almeida Silva, Tobias Engel, Cristina R Reschke, Ronan M Conroy, Elena Langa, David C Henshall
Animal models of status epilepticus are important tools to understand the pathogenesis of epileptic brain injury and evaluate potential seizure-suppressive, neuroprotective, and antiepileptogenic treatments. Focal elicitation of status epilepticus by intraamygdala kainic acid in mice produces unilateral hippocampal damage and the emergence of spontaneous recurrent seizures after a short latent period. The model has been characterized in C57BL/6, BALB/c, and SJL mice where strain-specific differences were found in the extent of hippocampal damage...
October 13, 2016: Epilepsy & Behavior: E&B
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
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
Motasem Melhem, Mohamed Abu-Farha, Dinu Antony, Ashraf Al Madhoun, Chiara Bacchelli, Fadi Alkayal, Irina AlKhairi, Sumi John, Mohamad Alomari, Phillip L Beales, Osama Alsmadi
OBJECTIVE: To characterize the underlying genetic and molecular defects in a consanguineous family with life-long blood disorder manifested with thrombocytopenia (low platelets count) and anemia. METHODS: Genetic linkage analysis, exome sequencing and functional genomics were carried out to identify and characterize the defective gene. RESULTS: We identification of a novel truncation mutation (p.C108*) in Chromosome 6 Open Reading Frame 25 (C6orf25) gene in this family...
October 15, 2016: European Journal of Haematology
Tainã Rapp Py-Daniel, Anderson Kennedy Soares De-Lima, Fabiano Campos Lima, Aline Pic-Taylor, Osmindo Rodrigues Pires Junior, Antonio Sebben
The mouse, chicken, African clawed frog and zebrafish are considered "model organisms" due to their extensive embryological and genetic characterization. However they are far from representative of known diversity, impairing phylogenetic analyses of developmental patterns. Since squamates have historically received limited attention in developmental studies, we here describe the developmental sequence for Tropidurus torquatus, and provide the first post-ovipositional developmental series for the lizard family Tropiduridae...
October 14, 2016: Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology
Nikolas M Eleftheriou, Jonas Sjölund, Matteo Bocci, Eliane Cortez, Se-Jin Lee, Sara I Cunha, Kristian Pietras
Angiogenesis occurs early in tumor development, sustains primary tumor growth and provides a route for metastatic escape. The TGF-β family receptors modulate angiogenesis via endothelial-cell specific pathways. Here we investigate the interaction of two such receptors, ALK1 and endoglin, in pancreatic neuroendocrine tumors (PanNET). Independently, ALK1 and endoglin deficiencies exhibited genetically divergent phenotypes, while both highly correlate to an endothelial metagene in human and mouse PanNETs. A concurrent deficiency of both receptors synergistically decreased tumor burden to a greater extent than either individual knockdown...
October 12, 2016: Oncotarget
Adrienne Wang, Jacob Mouser, Jason Pitt, Daniel Promislow, Matt Kaeberlein
Pediatric mitochondrial disorders are a devastating category of diseases caused by deficiencies in mitochondrial function. Leigh Syndrome (LS) is the most common of these diseases with symptoms typically appearing within the first year of birth and progressing rapidly until death, usually by 6-7 years of age. Our lab has recently shown that genetic inhibition of the mechanistic target of rapamycin (TOR) rescues the short lifespan of yeast mutants with defective mitochondrial function, and that pharmacological inhibition of TOR by administration of rapamycin significantly rescues the shortened lifespan, neurological symptoms, and neurodegeneration in a mouse model of LS...
October 11, 2016: Oncotarget
Paul F Lambert
Genetically engineered mice (GEMs) have provided valuable insights into the carcinogenic properties of various human tumor viruses, which, in aggregate, are etiologically associated with over 15% of all human cancers. This review provides an overview of seminal discoveries made through the use of GEM models for human DNA tumor viruses. Emphasis is placed on the discoveries made in the study of human papillomaviruses, Merkel cell carcinoma-associated polyomavirus, Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus, because GEMs have contributed extensively to our understanding of how these DNA tumor viruses directly contribute to human cancers...
September 29, 2016: Annual Review of Virology
Guillermo S Romano Ibarra, Biswajit Paul, Blythe D Sather, Patrick M Younan, Karen Sommer, John P Kowalski, Malika Hale, Barry Stoddard, Jordan Jarjour, Alexander Astrakhan, Hans-Peter Kiem, David J Rawlings
A naturally occurring 32-base pair deletion of the HIV-1 co-receptor CCR5 has demonstrated protection against HIV infection of human CD4(+) T cells. Recent genetic engineering approaches using engineered nucleases to disrupt the gene and mimic this mutation show promise for HIV therapy. We developed a megaTAL nuclease targeting the third extracellular loop of CCR5 that we delivered to primary human T cells by mRNA transfection. The CCR5 megaTAL nuclease established resistance to HIV in cell lines and disrupted the expression of CCR5 on primary human CD4(+) T cells with a high efficiency, achieving up to 80% modification of the locus in primary cells as measured by molecular analysis...
August 23, 2016: Molecular Therapy. Nucleic Acids
Thomas Naert, Robin Colpaert, Tom Van Nieuwenhuysen, Dionysia Dimitrakopoulou, Jannick Leoen, Jurgen Haustraete, Annekatrien Boel, Wouter Steyaert, Trees Lepez, Dieter Deforce, Andy Willaert, David Creytens, Kris Vleminckx
Retinoblastoma is a pediatric eye tumor in which bi-allelic inactivation of the Retinoblastoma 1 (RB1) gene is the initiating genetic lesion. Although recently curative rates of retinoblastoma have increased, there are at this time no molecular targeted therapies available. This is, in part, due to the lack of highly penetrant and rapid retinoblastoma animal models that facilitate rapid identification of targets that allow therapeutic intervention. Different mouse models are available, all based on genetic deactivation of both Rb1 and Retinoblastoma-like 1 (Rbl1), and each showing different kinetics of retinoblastoma development...
October 14, 2016: Scientific Reports
Christopher C Angelakos, Adam J Watson, W Timothy O'Brien, Kyle S Krainock, Thomas Nickl-Jockschat, Ted Abel
Sleep disturbances and hyperactivity are prevalent in several neurodevelopmental disorders, including autism spectrum disorders (ASDs) and attention deficit-hyperactivity disorder (ADHD). Evidence from genome-wide association studies indicates that chromosomal copy number variations (CNVs) are associated with increased prevalence of these neurodevelopmental disorders. In particular, CNVs in chromosomal region 16p11.2 profoundly increase the risk for ASD and ADHD, disorders that are more common in males than females...
October 14, 2016: Autism Research: Official Journal of the International Society for Autism Research
L Ozcan, I Tabas
The burden of type 2 diabetes and its major complication cardiovascular disease is rapidly increasing worldwide. Understanding the underlying pathogenic mechanisms of these diseases is crucial to develop novel therapeutics. Recent work using genetic and biochemical methods in mouse models and human samples have identified disturbed calcium signalling and endoplasmic reticulum stress as emerging factors involved in the pathogenesis of many metabolic diseases. In this review, we will highlight the specific roles of calcium signalling and endoplasmic reticulum stress response in the development of insulin resistance and atherosclerosis...
October 14, 2016: Journal of Internal Medicine
Yajing Zhai, Zhijun Dai, Hairong He, Fan Gao, Lihong Yang, Yalin Dong, Jun Lu
Molecular epidemiological research suggests that mouse double minute 4 (MDM4) polymorphisms may be associated with cancer susceptibility, but results remain controversial. To derive a more precise evaluation, we performed a PRISMA compliant meta-analysis focused on five single nucleotide polymorphisms (rs11801299, rs1380576, rs10900598, rs1563828, and rs4245739) of MDM4. Overall, 23 studies involving 22,218 cases and 55,033 controls were analyzed. The results showed that rs4245739 was significantly associated with a decreased cancer risk in the allelic (C vs...
October 11, 2016: Oncotarget
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