The Zebrafish Information Network: the zebrafish model organism database provides expanded support for genotypes and phenotypes

Sprague, Judy; Bayraktaroglu, Leyla; Bradford, Yvonne M.; Conlin, Tom; Dunn, Nathan; Fashena, David; Frazer, Ken; Haendel, Melissa; Howe, Douglas G.; Knight, Jonathan; Mani, Prita; Moxon, Sierra; Pich, Christian; Ramachandran, Sridhar; Schaper, Kevin; Segerdell, Erik; Shao, Xiang; Singer, Amy; Song, Peiran; Sprunger, Brock; Slyke, Ceri E. Van; Westerfield, Monte

doi:10.1093/nar/gkm956

Cited by 144 publications

(126 citation statements)

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“…Zebrafish have surged in importance as an animal model in almost every field of medicine, [9][10][11] owing to their publicly available genomic sequence, 12 their external fertilization, rapid development, accessibility of embryos (larvae) and the evolutionary conservation of the vertebrate body plan. Their precocious development of vision and remarkable evolutionary conservation of the eye make the zebrafish retina an excellent model for human visual disorders.…”

Section: Introductionmentioning

confidence: 99%

Gucy2f zebrafish knockdown – a model for Gucy2d-related leber congenital amaurosis

et al. 2012

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Mutations in retinal-specific guanylate cyclase (Gucy2d) are associated with Leber congenital amaurosis-1 (LCA1). Zebrafish offer unique advantages relative to rodents, including their excellent color vision, precocious retinal development, robust visual testing strategies, low cost, relatively easy transgenesis and shortened experimental times. In this study we will demonstrate the feasibility of using gene-targeting in the zebrafish as a model for the photoreceptor-specific GUCY2D-related LCA1, by reporting the visual phenotype and retinal histology resulting from Gucy2f knockdown. Gucy2f zebrafish LCA-orthologous cDNA was identified and isolated by PCR amplification. Its expression pattern was determined by whole-mount in-situ hybridization and its function was studied by gene knockdown using two different morpholino-modified oligos (MO), one that blocks translation of Gucy2f and one that blocks splicing of Gucy2f. Visual function was assessed with an optomotor assay on 6-days-postfertilization larvae, and by analyzing changes in retinal histology. Gucy2f knockdown resulted in significantly lower vision as measured by the optomotor response compared with uninjected and control MO-injected zebrafish larvae. Histological changes in the Gucy2f-knockdown larvae included loss and shortening of cone and rod outer segments. A zebrafish model of Gucy2f-related LCA1 displays early visual dysfunction and photoreceptor layer dystrophy. This study serves as proof of concept for the use of zebrafish as a simple, inexpensive model with excellent vision on which further study of LCA-related genes is possible. Keywords: leber congenital amaurosis; animal model; GUCY2D; optomotor assay INTRODUCTION Leber congenital amaurosis (LCA) is a family of severe, early-onset, autosomal-recessive forms of pediatric blindness. LCA has been linked to more than 16 genes, often exhibiting clinical heterogeneity. 1,2 LCA1 is caused by mutations in the gene GUCY2D, which encodes the retinal Gucy2d-1 (GC1) and accounts for B20% of all cases of LCA. 3 LCA2 is caused by mutations in the RPE65 gene, which is expressed in the retinal pigment epithelium. Breakthrough research has demonstrated visual improvement following gene therapy trials in humans with LCA2. 4,5 Human trials relied on a decade of proof-of-concept studies in canine and rodent models. 6-8 Unlike LCA2, in which gene therapy is aimed at correcting an RPE defect, searching for gene therapy for LCA1 will involve an attempt at treating the photoreceptors. European Journal of Human GeneticsResearch in inherited retinal disease relies heavily on animal models, commonly mammals such as mice and dogs. These animal models have significant advantages, including the availability of knockout technology. Two specific drawbacks slow the applicability of rodent or canine models for study of relatively rare genetic diseases such as LCA and other retinal dystrophies. The first difficulty is the high cost and length of time required to create a new knockout line; thus, it is applicable only for comm...

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Section: Introductionmentioning

confidence: 99%

Gucy2f zebrafish knockdown – a model for Gucy2d-related leber congenital amaurosis

et al. 2012

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“…Recently, Robu et al (56) have proposed that an increase in p53-dependent cell death is an off-target nonspecific effect of some MOs, and they showed that it can be rescued by co-injection of a p53-MO of the same sequence. Using a MO to empty spiracles homeobox 3 (emx3-MO), which targets a transcription factor important for brain development (57) and has been previously shown to induce such nonspecific cell death, 4 we saw similar levels of acridine orange staining as in surf1-MO-injected fish. As previously observed by our colleagues, co-injection of the same p53-MO with emx3-MO ameliorated the apoptosis detectable with acridine orange staining in a dose-dependent manner.…”

Section: Reduction Of Either Coxva or Surf1mentioning

confidence: 82%

Early Developmental Pathology Due to Cytochrome c Oxidase Deficiency Is Revealed by a New Zebrafish Model

Baden

Murray²,

Capaldi

et al. 2007

Journal of Biological Chemistry

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Deficiency of cytochrome c oxidase (COX) is associated with significant pathology in humans. However, the consequences for organogenesis and early development are not well understood. We have investigated these issues using a zebrafish model. COX deficiency was induced using morpholinos to reduce expression of CoxVa, a structural subunit, and Surf1, an assembly factor, both of which impaired COX assembly. Reduction of COX activity to 50% resulted in developmental defects in endodermal tissue, cardiac function, and swimming behavior. Cellular investigations revealed different underlying mechanisms. Apoptosis was dramatically increased in the hindbrain and neural tube, and secondary motor neurons were absent or abnormal, explaining the motility defect. In contrast, the heart lacked apoptotic cells but showed increasingly poor performance over time, consistent with energy deficiency. The zebrafish model has revealed tissue-specific responses to COX deficiency and holds promise for discovery of new therapies to treat mitochondrial diseases in humans.Cytochrome c oxidase (COX) 2 is the terminal enzyme in the mitochondrial respiratory chain. Embedded in the inner mitochondrial membrane, COX couples the vectoral movement of protons across the inner membrane to the transfer of electrons from reduced cytochrome c to molecular oxygen. Mammalian COX consists of 13 subunits, 10 of which (COXIV-COXVIII) are encoded by nuclear DNA. The other three subunits (COXI, COXII, and COXIII) are encoded by the mitochondrial DNA (mtDNA) and constitute the hydrophobic/catalytic core of the enzyme. Assembly of COX is a complicated process involving multiple assembly factors and chaperones, including COX10 -11, COX15-20, COX23, SCO1, SCO2, and SURF1 (1). Deficiency in COX activity is associated with significant pathology usually affecting highly metabolic tissues, including brain, muscle, and eyes (2, 3). For example, COX deficiency is commonly associated with Leigh syndrome, an early-onset disorder resulting in progressive central nervous system degeneration and early lethality (4, 5). The majority of cases of COX-deficient Leigh syndrome are a result of mutations in SURF1, which encodes a COX assembly factor (6, 7). Mutations in SURF1 impair the incorporation of subunit II, resulting in a buildup of an early COX assembly intermediate, decrease in other COX subunits, and a decrease in COX activity (8 -11). COX deficiency may also be complicated by cardiac pathology, including hypertrophic and dilated cardiomyopathies (12, 13), and conduction defects (14).COX deficiency is detrimental during the prenatal period as well. The incidence of this disorder has prompted the application of COX activity assays to prenatal samples obtained by chorionic villus biopsy and amniocentesis in specific cases (15,16). Prenatal diagnostics of this type have preparatory value for parents and physicians and may also be used to explain previous pregnancy losses (17). However, our incomplete understanding of the metabolic requirements of different tissues and ...

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“…The E+Q approach is referred to as 'postcomposition' , reflecting the composition of compound terms from components. It is used in the EuroPhenome mouse phenotype database (www.europhenome.org/) to describe raw phenotype data from highthroughput phenotyping experiments (Beck et al, 2009;Morgan et al, 2010), and in some model organism databases such as ZFIN and FlyBase (Drysdale, 2008;Sprague et al, 2008). For example, to describe the phenotype of Sox9 mutants, MGI uses the pre-composed term MP:0005587 (abnormal Meckel's cartilage) and ZFIN uses the E+Q approach -entity, ZFA:0001205 (Meckel's cartilage); quality, PATO:000587 (decreased size).…”

Section: Special Articlementioning

confidence: 99%

Phenotype ontologies for mouse and man: bridging the semantic gap

Schofield

Gkoutos

Gruenberger³

et al. 2010

Disease Models &Amp; Mechanisms

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A major challenge of the post-genomic era is coding phenotype data from humans and model organisms such as the mouse, to permit the meaningful translation of phenotype descriptions between species. This ability is essential if we are to facilitate phenotype-driven gene function discovery and empower comparative pathobiology. Here, we review the current state of the art for phenotype and disease description in mice and humans, and discuss ways in which the semantic gap between coding systems might be bridged to facilitate the discovery and exploitation of new mouse models of human diseases.publishersversionPeer reviewe

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The Zebrafish Information Network: the zebrafish model organism database provides expanded support for genotypes and phenotypes

Cited by 144 publications

References 8 publications

Gucy2f zebrafish knockdown – a model for Gucy2d-related leber congenital amaurosis

Gucy2f zebrafish knockdown – a model for Gucy2d-related leber congenital amaurosis

Early Developmental Pathology Due to Cytochrome c Oxidase Deficiency Is Revealed by a New Zebrafish Model

Phenotype ontologies for mouse and man: bridging the semantic gap

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