A genetic screen in zebrafish identifies the mutants<i>vps18, nf2</i>and<i>foie gras</i>as models of liver disease

Sadler, Kirsten C.; Amsterdam, Adam; Soroka, Carol J.; Boyer, James L.; Hopkins, Nancy

doi:10.1242/dev.01918

Cited by 170 publications

(167 citation statements)

References 60 publications

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“…A screen in zebrafish by using retroviral insertional mutagenesis identified nearly 1/4 of the genes that are essential for embryogenesis, and the mutated gene has been identified in every line (21). Streptavidin linked to the fluorophore CY3 (CY3-SA) effectively labels the liver in fixed embryos and was used to screen 294 of these lines for mutants with liver size defects (30), and the hi 272 was chosen for further analysis. Fig.…”

Section: Resultsmentioning

confidence: 99%

“…21. CY3-SA staining was performed as described (30). Mutants that were healthy on day 5 and had little or no liver tissue staining with CY3-SA were scored as small-for-size liver mutants.…”

Section: Methodsmentioning

confidence: 99%

“…Day 5 embryos were processed for in situ hybridization by using a probe mixture containing dioxygeninlabeled anti-sense fabp10 (30) and insulin, prepared as described in ref. 47.…”

Section: Methodsmentioning

confidence: 99%

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Liver growth in the embryo and during liver regeneration in zebrafish requires the cell cycle regulator, uhrf1

Sadler

Krahn

Gaur

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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160

192

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In contrast to the deregulated hepatocellular division that is a feature of many hepatic diseases and malignancies, physiologic liver growth during embryonic development and after partial hepatectomy (PH) in adults is characterized by tightly controlled cell proliferation. We used forward genetic screening in zebrafish to test the hypothesis that a similar genetic program governs physiologic liver growth during hepatogenesis and regeneration after PH. We identified the uhrf1 gene, a cell cycle regulator and transcriptional activator of top2a expression, as required for hepatic outgrowth and embryonic survival. By developing a methodology to perform PH on adult zebrafish, we found that liver regeneration in uhrf1 ؉/؊ adult animals is impaired. uhrf1 transcript levels dramatically increase after PH in both mice, and zebrafish and top2a is not up-regulated in uhrf1 ؉/؊ livers after PH. This indicates that uhrf1 is required for physiologic liver growth in both embryos and adults and illustrates that zebrafish livers regenerate.hepatic outgrowth ͉ hepatogenesis ͉ partial hepatectomy T he liver's capacity to regenerate after acute injury allows for the full restoration of liver mass and function. In the most reliable model to study liver regeneration in rodents, Ϸ70% of the liver mass is removed with partial hepatectomy (PH), resulting in the reentry of the normally quiescent hepatocytes into the cell cycle (1). Within a week of this procedure, the presurgical liver mass is restored (2). Whereas pathologic liver growth is characterized by uncontrolled cell division, physiologic liver growth during PH-induced liver regeneration is a tightly regulated process. Hepatic outgrowth, the final stage of liver development during which the liver bud expands, is another example of physiologic liver growth. There is very little known regarding the process that controls hepatic outgrowth in the embryo, and with decades of research on liver regeneration, the genetic requirements of physiologic liver growth remains an active area of scientific inquiry.Studies with knockout mice have identified a few genes that are essential for both hepatic outgrowth and regeneration; of these, none are liver-specific. For example, a liver specific knockout of c-jun results in defective liver regeneration (3), whereas homozygous c-jun deletion results in embryonic lethality and hypoplastic livers (4, 5). Similar studies have shown that the hepatocyte growth factor/c-met (6-8), ␤-catenin (9), and TNF␣ (10-12) pathways also regulate physiologic liver growth in embryos and adults. Comparison of the gene expression profiles in regenerating and embryonic livers has identified a handful of genes that are coregulated during both processes (13, 14); however, the functional significance of these findings has not yet been addressed.Zebrafish present an excellent system for such genetic studies. The robust regenerative potential of adult zebrafish is well established (15), and PH-induced liver regeneration has been reported in trout (16), suggesting similar st...

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Section: Resultsmentioning

confidence: 99%

“…21. CY3-SA staining was performed as described (30). Mutants that were healthy on day 5 and had little or no liver tissue staining with CY3-SA were scored as small-for-size liver mutants.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Liver growth in the embryo and during liver regeneration in zebrafish requires the cell cycle regulator, uhrf1

Sadler

Krahn

Gaur

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

160

192

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“…Larvae have started to be used in genetic and chemical screenings for the development of drugs targeting obesity (Jones et al 2008, Chu et al 2012, and NAFLD and NASH have been reported in various fish models (Asaoka et al 2013). For example, fgr mutant (Sadler et al 2005) and transgenic zebrafish expressing the hepatitis B virus X protein (Shieh et al 2010) display most of the mammalian NASH features. Furthermore, NAFLD can be induced in healthy zebrafish both chemically, with tamoxifen (Anezaki et al 2009), and with a high-fat content diet (Oka et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Liver immune responses to inflammatory stimuli in a diet-induced obesity model of zebrafish

Forn-Cuní¹,

Varela²,

Fernández-Rodrı́guez³

et al. 2014

Journal of Endocrinology

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Obesity-and metabolic syndrome-related diseases are becoming important medical challenges for the western world. Non-alcoholic fatty liver disease (NAFLD) is a manifestation of these altered conditions in the liver, and inflammation appears to be a factor that is tightly connected to its evolution. In this study, we used a diet-induced obesity approach in zebrafish (Danio rerio) based on overfeeding to analyze liver transcriptomic modulation in the disease and to determine how obesity affects the immune response against an acute inflammatory stimulus such as lipopolysaccharide (LPS). Overfed zebrafish developed an obese phenotype, showed signs of liver steatosis, and its modulation profile resembled that observed in humans, with overexpression of tac4, col4a3, col4a5, lysyl oxidases, and genes involved in retinoid metabolism. In response to LPS, healthy fish exhibited a typical host defense reaction comparable to that which occurs in mammals, whereas there was no significant gene modulation when comparing expression in the liver of LPS-stimulated and non-stimulated obese zebrafish at the same statistical level. The stimulation of obese fish represents a double-hit to the already damaged liver and can help understand the evolution of the disease. Finally, a comparison of the differential gene activation between stimulated healthy and obese zebrafish revealed the expected difference in the metabolic state between healthy and diseased liver. The differentially modulated genes are currently being studied as putative new pathological markers in NAFLD-stimulated liver in humans.

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“…Several proteins are responsible for liver metabolism, including uncoupling protein 2, phosphoenolpyruvate carboxykinase (pck1) and carnitine palmitoyltransferase 1A (Gut et al 2013). Staining with Oil Red O allows to detect adipocytes close to the gut and pancreas of zebrafish (Sadler et al 2005). Intestinal lipids can also be observed in vivo using fluorescently labelled fatty acid analogues (Farber et al 2001).…”

Section: Metabolic Diseasesmentioning

confidence: 99%

Zebrafish: an animal model for research in veterinary medicine

Nowik¹,

Podlasz²,

Jakimiuk³

et al. 2015

Polish Journal of Veterinary Sciences

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The zebrafish (Danio rerio) has become known as an excellent model organism for studies of vertebrate biology, vertebrate genetics, embryonal development, diseases and drug screening. Nevertheless, there is still lack of detailed reports about usage of the zebrafish as a model in veterinary medicine. Comparing to other vertebrates, they can lay hundreds of eggs at weekly intervals, externally fertilized zebrafish embryos are accessible to observation and manipulation at all stages of their development, which makes possible to simplify the research techniques such as fate mapping, fluorescent tracer time-lapse lineage analysis and single cell transplantation. Although zebrafish are only 2.5 cm long, they are easy to maintain. Intraperitoneal and intracerebroventricular injections, blood sampling and measurement of food intake are possible to be carry out in adult zebrafish. Danio rerio is a useful animal model for neurobiology, developmental biology, drug research, virology, microbiology and genetics. A lot of diseases, for which the zebrafish is a perfect model organism, affect aquatic animals. For a part of them, like those caused by Mycobacterium marinum or Pseudoloma neutrophila, Danio rerio is a natural host, but the zebrafish is also susceptible to the most of fish diseases including Itch, Spring viraemia of carp and Infectious spleen and kidney necrosis. The zebrafish is commonly used in research of bacterial virulence. The zebrafish embryo allows for rapid, non-invasive and real time analysis of bacterial infections in a vertebrate host. Plenty of common pathogens can be examined using zebrafish model: Streptococcus iniae, Vibrio anguillarum or Listeria monocytogenes. The steps are taken to use the zebrafish also in fungal research, especially that dealing with Candida albicans and Cryptococcus neoformans. Although, the zebrafish is used commonly as an animal model to study diseases caused by external agents, it is also useful in studies of metabolic disorders including fatty liver disease and diabetes. The zebrafish is also a valuable tool as a model in behavioral studies connected with feeding, predator evasion, habituation and memory or lateralized control of behavior. The aim of the present article is to familiarize the reader with the possibilities of Danio rerio as an experimental model for veterinary medicine.

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A genetic screen in zebrafish identifies the mutantsvps18, nf2andfoie grasas models of liver disease

Cited by 170 publications

References 60 publications

Liver growth in the embryo and during liver regeneration in zebrafish requires the cell cycle regulator, uhrf1

Liver growth in the embryo and during liver regeneration in zebrafish requires the cell cycle regulator, uhrf1

Liver immune responses to inflammatory stimuli in a diet-induced obesity model of zebrafish

Zebrafish: an animal model for research in veterinary medicine

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