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Zebrafish disease modelling

Shu Meng, Qilin Gu, Xiaojie Yang, Jie Lv, Iris Owusu, Gianfranco Matrone, Kaifu Chen, John P Cooke, Longhou Fang
Background -Angiogenesis is integral for embryogenesis, and targeting angiogenesis improves the outcome of many pathological conditions in patients. TBX20 is a crucial transcription factor for embryonic development, and its deficiency is associated with congenital heart disease. However, the role of TBX20 in angiogenesis has not been described. Methods -Loss- and gain-of-function approaches were used to explore the role of TBX20 in angiogenesis both in vitro and in vivo Angiogenesis gene array was used to identify key downstream targets of TBX20...
March 15, 2018: Circulation
Christopher J Lambert, Briana C Freshner, Arlen Chung, Tamara J Stevenson, D Miranda Bowles, Raheel Samuel, Bruce K Gale, Joshua L Bonkowsky
Zebrafish are a valuable model organism in biomedical research. Their rapid development, ability to model human diseases, utility for testing genetic variants identified from next-generation sequencing, amenity to CRISPR mutagenesis, and potential for therapeutic compound screening, has led to their wide-spread adoption in diverse fields of study. However, their power for large-scale screens is limited by the absence of automated genotyping tools for live animals. This constrains potential drug screen options, limits analysis of embryonic and larval phenotypes, and requires raising additional animals to adulthood to ensure obtaining an animal of the desired genotype...
2018: PloS One
Ivan Bozic, Xiaoyue Li, Yuankai Tao
The zebrafish is a robust model for studying human ophthalmic function and disease because of its fecundity, life-cycle, and similarities between its retinal structure and the human retina. Here, we demonstrate longitudinal in vivo imaging of retinal structure using optical coherence tomography (OCT) and noninvasive retinal vascular perfusion imaging using OCT angiography (OCT-A) in zebrafish. In addition, we present methods for retinal vascular segmentation and biometry to quantify vessel branch length, curvature, and angle...
March 1, 2018: Biomedical Optics Express
Xin Chen, Yufei Fu, Hongfei Xu, Peng Teng, Qiong Xie, Yiran Zhang, Caochong Yan, Yiqiao Xu, Chunqi Li, Jianying Zhou, Yiming Ni, Weidong Li
Lung cancer is the leading cause of cancer-related death worldwide. Epithelial-mesenchymal transition (EMT) promotes lung cancer progression and metastasis, especially in lung adenocarcinoma. Sex determining region Y-box protein 5 (SOX5) is known to stimulate the progression of various cancers. Here, we used immunohistochemical analysis to reveal that SOX5 levels were increased in 90 lung adenocarcinoma patients. The high SOX5 expression in lung adenocarcinoma and non-tumor counterparts correlated with the patients' poor prognosis...
February 16, 2018: Oncotarget
Ray Hu, Michael P Morley, Jeffrey Brandimarto, Nathan R Tucker, Victoria A Parsons, Sihai D Zhao, Benjamin Meder, Hugo A Katus, Frank Rühle, Monika Stoll, Eric Villard, François Cambien, Honghuang Lin, Nicholas L Smith, Janine F Felix, Ramachandran S Vasan, Pim van der Harst, Christopher Newton-Cheh, Jin Li, Cecilia E Kim, Hakon Hakonarson, Sridhar Hannenhalli, Euan A Ashley, Christine S Moravec, W H Wilson Tang, Marjorie Maillet, Jeffery D Molkentin, Patrick T Ellinor, Kenneth B Margulies, Thomas P Cappola
BACKGROUND: Inhibition of PKC-α (protein kinase C-α) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with PRKCA expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-α in human populations. METHODS AND RESULTS: We analyzed the cis expression quantitative trait locus for PRKCA marked by rs9912468 using 313 left ventricular specimens from European Ancestry patients...
March 2018: Circ Genom Precis Med
Heather Flanagan-Steet, Courtney Christian, Po-Nien Lu, Megan Aarnio-Peterson, Laura Sanman, Stephanie Archer-Hartmann, Parastoo Azadi, Matthew Bogyo, Richard A Steet
Cysteine cathepsins play roles during development and disease beyond their function in lysosomal protein turnover. Here, we leverage a fluorescent activity-based probe (ABP), BMV109, to track cysteine cathepsins in normal and diseased zebrafish embryos. Using this probe in a model of mucolipidosis II, we show that loss of carbohydrate-dependent lysosomal sorting alters the activity of several cathepsin proteases. The data support a pathogenic mechanism where TGF-ß signals enhance the proteolytic processing of pro-Ctsk by modulating the expression of chondroitin 4-sulfate (C4-S)...
March 13, 2018: Cell Reports
Juanjuan Zhao, Mathilda T M Mommersteeg
The Slit ligands and their Robo receptors are well-known for their roles during axon guidance in the central nervous system, but are still relatively unknown in the cardiac field. However, data from different animal models suggest a broad involvement of the pathway in many aspects of heart development, from cardiac cell migration and alignment, lumen formation, chamber formation, to the formation of the ventricular septum, semilunar and atrioventricular valves, caval veins and pericardium. Absence of one or more of the genes in the pathway results in defects ranging from bicuspid aortic valves to ventricular septal defects and abnormal venous connections to the heart...
March 10, 2018: Cardiovascular Research
Dechao Xu, Jiayi Lv, Liangliang He, Lili Fu, Ruikun Hu, Ying Cao, Changlin Mei
Polarity complexes, including the PAR (Partitioning-defective), CRB (Crumbs) and SCRIB (Scribble) complexes, are required for the physiologic establishment, stabilization, and maintenance of a functional apical-basolateral polarity. Inactivation of some of the polarity complexes results in cystic kidneys, and apical-basolateral polarity defects are commonly observed in autosomal-dominant polycystic kidney disease (ADPKD); however, little is known about the role that polarity complexes play in ADPKD. Here, we demonstrate that Scribble, a core protein of the SCRIB complex, is down-regulated in ADPKD cell lines and the zebrafish model of this disease ( pkd2 morphants)...
March 12, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Amrutha Swaminathan, Marilou Bouffard, Meijiang Liao, Sarah Ryan, Janis Bennion Callister, Stuart M Pickering-Brown, Gary Alan Barclay Armstrong, Pierre Drapeau
Large expansions of hexanucleotide GGGGCC (G4C2) repeats (hundreds to thousands) in the first intron of the chromosome 9 open reading frame 72 (C9orf72) locus are the strongest known genetic factor associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Different hypotheses exist about the underlying disease mechanism including loss-of-function by haploinsufficiency, toxicity arising as a result of RNA or dipeptide repeats (DPRs). Five different DPRs are produced by repeat-associated non-ATG-initiated (RAN) translation of the G4C2 repeats...
March 8, 2018: Human Molecular Genetics
Erzsebet Polyak, Julian Ostrovsky, Min Peng, Stephen D Dingley, Mai Tsukikawa, Young Joon Kwon, Shana E McCormack, Michael Bennett, Rui Xiao, Christoph Seiler, Zhe Zhang, Marni J Falk
Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials...
February 23, 2018: Molecular Genetics and Metabolism
Ann Kristin Frøyset, Amanda J Edson, Naouel Gharbi, Essa A Khan, Daniel Dondorp, Qing Bai, Ettore Tiraboschi, Maximiliano L Suster, Joanne B Connolly, Edward A Burton, Kari E Fladmark
DJ-1, a Parkinson's disease-associated protein, is strongly up-regulated in reactive astrocytes in Parkinson's disease. This is proposed to represent a neuronal protective response, although the mechanism has not yet been identified. We have generated a transgenic zebrafish line with increased astroglial DJ-1 expression driven by regulatory elements from the zebrafish GFAP gene. Larvae from this transgenic line are protected from oxidative stress-induced injuries as caused by MPP+ , a mitochondrial complex I inhibitor shown to induce dopaminergic cells death...
February 17, 2018: Redox Biology
Jennifer C Hocking, Jakub K Famulski, Kevin H Yoon, Sonya A Widen, Cassidy S Bernstein, Sophie Koch, Omri Weiss, Seema Agarwala, Adi Inbal, Ordan J Lehmann, Andrew J Waskiewicz
The eye primordium arises as a lateral outgrowth of the forebrain, with a transient fissure on the inferior side of the optic cup providing an entry point for developing blood vessels. Incomplete closure of the inferior ocular fissure results in coloboma, a disease characterized by gaps in the inferior eye and recognized as a significant cause of pediatric blindness. Here, we identify eight patients with defects in tissues of the superior eye, a congenital disorder that we term superior coloboma. The embryonic origin of superior coloboma could not be explained by conventional models of eye development, leading us to reanalyze morphogenesis of the dorsal eye...
March 9, 2018: PLoS Genetics
Alice Giuliodori, Giorgia Beffagna, Giulia Marchetto, Chiara Fornetto, Francesco Vanzi, Stefano Toppo, Nicola Facchinello, Mattia Santimaria, Andrea Vettori, Stefania Rizzo, Mila Della Barbera, Kalliopi Pilichou, Francesco Argenton, Gaetano Thiene, Natascia Tiso, Cristina Basso
Aims: Arrhythmogenic cardiomyopathy (AC) is an inherited heart disease characterized by life-threatening ventricular arrhythmias and fibro-fatty replacement of the myocardium. More than 60% of AC patients show pathogenic mutations in genes encoding for desmosomal proteins. By focusing our attention on the AC8 form, linked to the junctional protein Desmoplakin (DSP), we present here a zebrafish model of DSP deficiency, exploited to identify early changes of cell signalling in the cardiac region...
March 7, 2018: Cardiovascular Research
Guang-Ping Liu, Li-Xin Xiang, Tong Shao, Ai-Fu Lin, Jian-Zhong Shao
Peroxiredoxin 1 (Prdx1/Prx1), a ubiquitous antioxidant enzyme involved in preventing oxidative damage and maintaining redox homeostasis, is essential for various cellular activities. Extracellular Prdx1 also plays important roles in innate immune responses. However, little is known about the regulatory functions of Prdx1 in adaptive immunity. In the present study, we report the stimulatory role of Prdx1 in the initiation of adaptive humoral immunity in a zebrafish model. Administration of Prdx1 protein to zebrafish significantly induced the expression of TNF-α, IL-1β, and IL-6 by the Toll-like-receptor-4a-mediated NF-κB signaling pathway and enhanced the activation of MHC-II+ antigen-presenting cells, CD4+ T cells, and mIgM+ B cells...
March 5, 2018: Developmental and Comparative Immunology
Cheri M Ackerman, Peter K Weber, Tong Xiao, Bao Thai, Tiffani J Kuo, Emily Zhang, Jennifer Pett-Ridge, Christopher J Chang
Copper is essential for eukaryotic life, and animals must acquire this nutrient through the diet and distribute it to cells and organelles for proper function of biological targets. Indeed, mutations in the central copper exporter ATP7A contribute to a spectrum of diseases, including Menkes disease, with symptoms ranging from neurodegeneration to lax connective tissue. As such, a better understanding of the fundamental impacts of ATP7A mutations on in vivo copper distributions is of relevance to those affected by these diseases...
March 6, 2018: Metallomics: Integrated Biometal Science
Kathryn E Hendee, Elena A Sorokina, Sanaa S Muheisen, Linda M Reis, Rebecca C Tyler, Vujica Markovic, Goran Cuturilo, Brian A Link, Elena V Semina
The PITX2 (paired-like homeodomain 2) gene encodes a bicoid-like homeodomain transcription factor linked with several human disorders. The main associated congenital phenotype is Axenfeld-Rieger syndrome, type 1 (ARS), an autosomal dominant condition characterized by variable defects in the anterior segment of the eye, an increased risk of glaucoma, craniofacial dysmorphism and dental and umbilical anomalies; in addition to this, one report implicated PITX2 in ring dermoid of the cornea and a few others described cardiac phenotypes...
March 1, 2018: Human Molecular Genetics
Priya Outtandy, Claire Russell, Robert Kleta, Detlef Bockenhauer
Kidney disease is a global problem with around three million people diagnosed in the UK alone and the incidence is rising. Research is critical to develop better treatments. Animal models can help to better understand the pathophysiology behind the various kidney diseases and to screen for therapeutic compounds, but the use especially of mammalian models should be minimised in the interest of animal welfare. Zebrafish are increasingly used, as they are genetically tractable and have a basic renal anatomy comparable to mammalian kidneys with glomerular filtration and tubular filtration processing...
March 3, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Yibo Zhang, Zhiwei Zhang, Wei Ge
Homology-directed recombination (HDR)-mediated genome editing is a powerful approach for both basic functional study and disease modeling. Although some studies have reported HDR-mediated precise editing in non-rodent models, the efficiency of establishing pure mutant animal lines that carry specific amino acid substitutions remains low. Furthermore, because the efficiency of nonhomologous end joining (NHEJ)-induced insertion and deletion (indel) mutations is normally much higher than that of HDR-induced point mutations, it is often difficult to identify the latter in the background of indel mutations...
March 2, 2018: Journal of Biological Chemistry
Donglai Sheng, Kelvin See, Xu Hu, Dongliang Yu, Yuying Wang, Qinliu Liu, Fei Li, Minxia Lu, Jing Zhao, Jianjun Liu
As a protein with complex domain structure and roles in kinase, GTPase and scaffolding, LRRK2 is believed to be an important orchestration node leading to several cascades of signal transduction rather than one specific pathway. LRRK2 variants were found to be associated with Parkinson's disease, Crohn's disease and leprosy. Here we disrupt LRRK2 in zebrafish and found hyperactivity rather than hypoactivity in adult zebrafish mutants. By RNA-seq we found genes involved in infectious disease and immunological disease were notably affected...
February 27, 2018: Biochemical and Biophysical Research Communications
Nicole Endlich, Felix Kliewe, Frances Kindt, Katharina Schmidt, Ahmed M Kotb, Nadine Artelt, Maja T Lindenmeyer, Clemens D Cohen, Franziska Döring, Andreas W Kuss, Kerstin Amann, Marcus J Moeller, Nazanin Kabgani, Antje Blumenthal, Karlhans Endlich
Dedifferentiation and loss of podocytes are the major cause of chronic kidney disease. Dach1, a transcription factor that is essential for cell fate, was found in genome-wide association studies to be associated with the glomerular filtration rate. We found that podocytes express high levels of Dach1 in vivo and to a much lower extent in vitro. Parietal epithelial cells (PECs) that are still under debate to be a type of progenitor cell for podocytes expressed Dach1 only at low levels. The transfection of PECs with a plasmid encoding for Dach1 induced the expression of synaptopodin, a podocyte-specific protein, demonstrated by immunocytochemistry and Western blot...
March 2, 2018: Journal of Cellular and Molecular Medicine
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