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PubMed2004

Zebrafish as a pharmacological tool: the how, why and when.

Zebrafish combine the relevance of a vertebrate with the scalability of an invertebrate. They can live in 96-well plate format and readily absorb chemicals from the water. These features have stimulated the use of zebrafish by medical researchers to model human disease and then assess the action of compounds in a whole organism. Examples of the power of this system have been illustrated with the cloning of zebrafish human ether-a-go-go-related gene (HERG), which shows near 100% homology in key domains, and the associated ability to identify drugs that prolong the QT interval both rapidly and with tiny amounts (micrograms) of compound.

Animals↗

PubMed2004

Studies on chilling sensitivity of zebrafish (Danio rerio) oocytes.

Human activity in the last few decades has had a devastating effect on the diversity of fresh water and marine fish. Further decline of fish population may have serious economic and ecological consequences. One of the most promising techniques to preserve fish population is to cryopreserve their germ cells. Cryopreservation has been successfully applied to fish sperm of many species, but there has been no success with fish embryo cryopreservation and fish oocyte cryopreservation has never been studied systematically. The aim of this study is to investigate the chilling sensitivity of fish oocytes. Experiments were conducted with zebrafish stage III (vitellogenic) and stage V (mature) oocytes, which were chilled at 10, 5, 0, -5 or -10 degrees C for 15 or 60 min using a low temperature bath. Control oocytes were kept at room temperature at 22 degrees C. Oocyte viability was assessed using three different methods: trypan blue staining (TB), thiazolyl blue tetrazolium bromide (MTT) staining and observation of germinal vesicle breakdown (GVBD). The results showed that zebrafish oocyte are very sensitive to chilling and their survival decreased with decreasing temperature and increasing exposure time periods. Normalised survivals assessed with TB staining after exposure to 0, -5 or -10 degrees C for 15 or 60 min were 90.1+/-6.0, 77.8+/-7.6, and 71.2+/-9.3%, and 60.2+/-3.8, 49.6+/-6.7, and 30.4+/-3.0%, respectively. The study found that the sensitivity of viability assessment methods increase in the order of MTT < TB < GVBD. It was found that stage III oocytes were more susceptible to chilling than stage V oocytes, and that individual female had a significant influence (p < 0.0001) on oocyte chilling sensitivity. Zebrafish oocyte chilling sensitivity may also be one of the limiting factors for development of protocol of their cryopreservation.

Animals↗

PubMed2005

Zebrafish IkappaB kinase 1 negatively regulates NF-kappaB activity.

The IkappaB kinase (IKK) activity is critical for processing IkappaB inhibitory proteins and activating the NF-kappaB signaling, which is involved in a series of physiological and developmental steps in vertebrates. The IKK activity resides in two catalytic subunits, IKK1 and IKK2, and two regulatory subunits, NEMO and ELKS. IKK2 is the major cytokine-responsive IkappaB kinase because depletion of IKK1 does not interfere with the IKK activity. In fact, IKK1-/- mice display morphological abnormalities that are independent of its kinase activity and NF-kappaB activation. Hence, using zebrafish (Danio rerio) as a model, we examined the evolutionary role of IKK1 in modulating NF-kappaB. Ikk1-/- zebrafish embryos present head and tail malformations and, surprisingly, show upregulation of NF-kappaB-responsive genes and increased NF-kappaB-dependent apoptosis. Overexpression of ikk1 leads to midline structure defects that resemble NF-kappaB blockage in vivo. Zebrafish Ikk1 forms complexes with NEMO that represses NF-kappaB in vertebrate cells. Indeed, truncation of its NEMO binding domain (NBD) restores NF-kappaB-dependent transcriptional activity and, consequently, the ikk1-overexpressing phenotype. Here, we report that Ikk1 negatively regulates NF-kappaB by sequestering NEMO from active IKK complexes, indicating that IKK1 can function as a repressor of NF-kappaB.

Animals↗

PubMed2026

Neurodevelopmental toxicity of 2-(Methylthio)benzothiazole (MTBT) in zebrafish: Insights into PTGS2- associated dysregulation of the neuroactive ligand-receptor interaction pathway.

2-(Methylthio)benzothiazole (MTBT), an important derivative of benzothiazoles, has extensive applications in industrial processes, pharmaceuticals, and environmental monitoring. It can enter aquatic environments through surface runoff and has been detected at relatively high concentrations in various environmental systems. However, studies investigating the aquatic toxicity of MTBT remain limited. In this study, zebrafish embryos were exposed to MTBT at concentrations of 0, 10, 100, and 1000 μg/L for 144 h to evaluate its developmental and neurotoxic effects. MTBT exposure significantly reduced the survival rate, hatching rate, spontaneous movement, and body length of zebrafish larvae. MTBT also impaired locomotor behavior, reduced fluorescence of Tg(huc:eGFP) larvae in the central nervous system and inhibited motor neuron axonal development. Protein-protein interaction network and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated that MTBT-induced neurotoxicity may be associated with disruption of the neuroactive ligand-receptor interaction pathway. Further validation experiments revealed that MTBT induced oxidative stress, inflammation, and apoptosis, suggesting that these adverse effects may underlie its neurodevelopmental toxicity. Collectively, these findings provide biological evidence that MTBT induces neurodevelopmental toxicity in zebrafish larvae and suggest that dysregulation of the PTGS2-related neuroactive ligand-receptor interaction pathway may be involved in this process.

2-(Methylthio)benzothiazole (MTBT)↗

PubMed2004

Abundant corneal gelsolin in Zebrafish and the 'four-eyed' fish, Anableps anableps: possible analogy with multifunctional lens crystallins.

The cornea accumulates high proportions (can be up to 50%) of taxon-specific, water-soluble, cytoplasmic proteins (often enzymes) that have been considered analogous to the multifunctional lens crystallins. We have shown that gelsolin (an actin-severing protein) is the major water-soluble corneal protein of the zebrafish (Danio rerio) and the 'four-eyed' fish (Anableps anableps). Each Anableps eye contains one lens, an aquatic ventral cornea with an epithelium comprising 5-7 cell layers, and an air-exposed flatter dorsal cornea with an epithelium comprising >20 cell layers and appreciably enriched with glycogen. Gelsolin accounts for 38 and 21% of the dorsal and ventral cornea, respectively, suggesting that the abundance of gelsolin in the cornea is not incompatible with its function in air. The thicker, glycogen-enriched, air-exposed dorsal cornea may protect against UV irradiation and desiccation. Gelsolin comprises approximately 50% of the 5 cell-layer thick aquatic corneal epithelium of zebrafish. Reported zebrafish ESTs have indicated the presence of a second gelsolin gene in this species. We show by RT-PCR that the abundant corneal gelsolin (also expressed weakly in lens) (C/L-gelsolin) is also expressed in early development and differs from a ubiquitously expressed gelsolin (U-gelsolin) that is not specialized for cornea. Microinjection tests showed that overexpression of C/L-gelsolin dorsalizes the embryo and can lead to axis duplication, while interruption of C/L-gelsolin expression with a specific morpholino oligonucleotide ventralizes the embryo and interferes with brain and eye development. The evidence that C/L-gelsolin participates in the bone morphogenetic protein (BMP)/Smad dorsal-ventral signaling pathway is reviewed. Finally, we speculate that soluble C/L-gelsolin:actin complexes in the cornea may be analogous to soluble alphaA:alphaB-crystallin complexes in the lens. Together, our data are consistent with an analogy between the abundance of gelsolin in fish corneas and taxon-specific multifunctional crystallins in lenses.

Animals↗

PubMed2005

Retinal regional differences in photoreceptor cell death and regeneration in light-lesioned albino zebrafish.

Teleost fish regenerate retinal cells from a population of inner nuclear layer (INL) stem cells. To characterize photoreceptor regeneration in zebrafish (Danio rerio), adult albino fish were subjected to constant intense light to cause photoreceptor cell death. Retinal morphometry was performed on histological sections of control and light-lesioned albino retinas to compare the extent of light damage in the ventral, central and dorsal retinal regions. In addition, opsin immunohistochemistry and TUNEL were used to compare photoreceptor cell death in these different retinal areas, while PCNA immunolabeling quantified the cell proliferation that precedes the photoreceptor regeneration. Transgenic albino; Tg(alpha1-tubulin:egfp) zebrafish were also exposed to the intense light in order to examine regeneration-related gene expression changes. The light-lesioned retinas are characterized by extensive rod and cone photoreceptor cell death in the central and dorsal regions. In contrast, many of the rods and cones survive in the ventral retina. The highest levels of INL cell proliferation, which occurs subsequent to photoreceptor death, correspond to the retinal regions that suffer the greatest levels of photoreceptor damage. In the ventral retina, where photoreceptor cell death is minimal, cell proliferation is confined to the ONL. In addition, EGFP expression from the alpha1-tubulin promoter is increased in Müller glial cells in the light-damaged central and dorsal retina, while transgene expression in the ventral retina is restricted to small, round INL cells. Furthermore, expression of the HuC/D neuronal antigen is detected in a subpopulation of the Müller cells in the light-damaged superior retinal region. These data demonstrate that adult albino zebrafish display retinal regional differences in photoreceptor cell death and in the regeneration-related INL cell proliferation response. The high levels of INL cell proliferation and alpha1-tubulin:egfp transgene expression in the Müller cells may be graded in response to the degree of photoreceptor cell death. This suggests that the levels of photoreceptor damage may directly influence cell responses in the underlying retinal layers.

Animals↗

PubMed2006

Spectral sensitivity of melatonin suppression in the zebrafish pineal gland.

The pineal gland of the zebrafish (Danio rerio) is a clock-containing photoreceptive organ. Superfused pineal glands kept in darkness display rhythmic melatonin production that lasts for days, with high melatonin levels during the night and low levels during the day. Nocturnal light, however, evokes an acute suppression of melatonin synthesis in the photoreceptor cells. Towards characterizing zebrafish pineal photopigment that is involved in the acute melatonin suppression we have measured the spectral sensitivity of melatonin-suppression response in superfused pineal glands. The effect of 2 h light exposure of seven wavelengths (lambdaavg 408, 460, 512, 560, 608, 660 and 697+/-10-15 nm) at multiple irradiances (10(7)-10(14) photons/cm2/s) was determined, and an action spectrum was plotted. The resultant action spectrum provides evidence for the involvement of multiple photopigments in melatonin suppression. The most efficient melatonin-suppression response was achieved by exposure to light of around 512 nm; however, another peak of lower irradiance sensitivity was observed in the middle to long wavelengths. Opsins-specific RT-PCR analysis confirmed the expression of exo-rhodopsin and visual red-sensitive opsin in the pineal gland, while other zebrafish visual opsins as well as VA and VAL opsins were not detected. Dartnall monograms for exo-rhodopsin and visual red-sensitive opsin account for most but not all of the spectral sensitivity features. Therefore, additional pineal photopigments may contribute to the melatonin-suppression response in the pineal gland.

Animals↗

PubMed2004

Harnessing zebrafish for the study of white blood cell development and its perturbation.

Considerable progress has been made in understanding the molecular basis of normal white blood cell development and its perturbation in disease through the use of clinical studies and traditional animal and cell line models. Despite this, however, many questions are still being answered and white blood cell disorders, including leukemia and lymphoma, remain a significant health problem. The zebrafish (Danio rerio) has emerged as a powerful alternative vertebrate model for the study of development and disease. We review the recent application of zebrafish to the study of white blood cell development and its disruption, particularly leukemogenesis. Such studies have highlighted the overall conservation of these processes throughout vertebrates, and establish zebrafish as a useful experimental model. This organism is now poised to make an important contribution to our understanding of the underlying genetic control of white blood cell development and its disruption, as well as the identification of new therapeutic agents.

Animals↗

PubMed2005

Zebrafish as a model for myelopoiesis during embryogenesis.

Zebrafish produce nearly identical hematopoeitic cell lineages to those found in mammals and other higher vertebrates. As in mammals, blood cell development proceeds in distinct waves, constituting embryonic (primitive) and adult (definitive) hematopoiesis. The conservation of genes such as scl, pu.1, c/ebpalpha, mpo, l-plastin, and lysozyme C in myelopoiesis and the corresponding expression patterns in zebrafish suggests that shared genetic pathways regulate this complex developmental process. In the zebrafish model system, experimental approaches have been applied, including RNA in situ hybridization, morpholino injections, and the analysis of mutant and transgenic fish lines, leading to improved understanding of the regulation in vivo of key molecular pathways with conserved roles in vertebrate myelopoiesis.

Animals↗

PubMed2005

Transcriptional regulation of hematopoietic stem cell development in zebrafish.

The zebrafish (Danio rerio) is a well-established vertebrate model for studying hematopoiesis. The major advantages of this system include robust experimental techniques in both genetics and embryology, which have been utilized to model many aspects of human development and disease. Although much is known about the transcription factors involved in the terminal differentiation of peripheral blood lineages, little is known about the development and maintenance of the hematopoietic stem cell (HSC). This review will focus on the current knowledge of the transcriptional regulation of the HSC in the context of the zebrafish. Future studies using new technologies in the zebrafish model will enhance our understanding of the molecular networks regulating HSC pluripotency and differentiation.

Animals↗

PubMed2005

Requirements of myocyte-specific enhancer factor 2A in zebrafish cardiac contractility.

Myocyte-specific enhancer factor 2A (MEF2A) regulates a broad range of fundamental cellular processes including cell division, differentiation and death. Here, we tested the hypothesis that MEF2A is required in cardiac contractility employing zebrafish as a model organism. MEF2A is highly expressed in heart as well as somites during zebrafish embryogenesis. Knock-down of MEF2A in zebrafish impaires the cardiac contractility and results in sarcomere assembly defects. Dysregulation of cardiac genes in MEF2A morphants suggests that sarcomere assembly disturbances account for the cardiac contractile deficiency. Our studies suggested that MEF2A is essential in cardiac contractility.

Animals↗

PubMed2006

Identification, cloning and characterization of interleukin-17 and its family from zebrafish.

Cytokines are one of the major signaling molecules involved in immunity. Many of these cytokines have been isolated in vertebrates and found to play a significant role in host defense mechanism. Interleukin-17 (IL-17) family of genes are known to have pro-inflammatory actions and associated with specific disease conditions, these genes are conserved across vertebrate evolution. In this study, computational screening for the zebrafish (Danio rerio) genome resulted in identification of five contigs harboring IL-17 genes. Zebrafish cDNA encoding five IL-17 genes exhibited percentage identities of 19.3%-61.9% with that of human homologs. The molecules show conservation of cysteines, important for disulphide bonds for IL-17 molecules. The structural composition of these genes shows two introns and three exons except for IL-17D gene that has only one intron and two exons. Phylogenetic analysis using maximum parsimony algorithm showed that zebrafish IL-17 genes clustered well with other IL-17 homologs further proving the structural similarity with IL-17 genes from other organisms. Expression analysis by RT-PCR revealed expression of IL-17 genes in normal and stimulated tissues of kidney, spleen, gills and intestine. The expression of IL-17 in un-stimulated tissues indicates that these genes may play important roles in normal conditions as well.

Animals↗

PubMed2005

Analysis of the very large G-protein coupled receptor gene (Vlgr1/Mass1/USH2C) in zebrafish.

Very Large G-protein coupled Receptor-1 (VLGR1/Mass1/USH2C) is the largest known cell surface protein in vertebrates. Mutations in VLGR1 are associated with audiogenic epilepsy in mice and Usher syndrome (sensorineural deafness and retinitis pigmentosa) in humans. We characterized the zebrafish VLGR1 gene (vlgr1). It is 51% identical to human VLGR1 in amino acid sequence, but is 64% identical in the 7-transmembrane and cytoplasmic domains. It is 6199 amino acids in size and is encoded by a 19.2 kb mRNA. All introns correspond in location and phase to those of the human and mouse genes. In situ hybridization studies of zebrafish embryos demonstrate vlgr1 expression in the developing central nervous system, particularly in the hypothalamus, epiphysis and in the rhombic lips. Expression in the eye is associated with the optic nerve. Further studies using zebrafish may help ascertain the role of Vlgr1 in neural development.

Animals↗

PubMed2006

Genomic alterations upon integration of zebrafish L1 elements revealed by the TANT method.

Transposable elements, or transposons, constitute substantial portions of eukaryotic genomes and have contributed to the diversity and functions of the genomes. Bioinformatic analysis of target junctions of genomic transposon copies can provide insights into their mobility mechanisms and consequent genomic alterations, but definitive identification of the target junctions remains difficult despite the steady accumulation of genomic sequence information. To overcome this difficulty, we recently developed a method termed "the target analysis of nested transposons" (TANT), which anatomizes junction features of numerous genomic copies of transposons that reside within other transposons. Whereas the mammalian long interspersed nuclear element (LINE)-1 (L1), a retrotransposon, has been proposed to make a considerable impact on host genomes, the mobility and impact of non-mammalian L1s are poorly understood. In the present study, we analyzed genomic copies of zebrafish L1 elements by using the TANT method. Some copies exhibited the features of integration that are similar to those of mammalian L1s. The zebrafish L1 retrotransposition reaction, however, frequently truncated the target-site DNA by up to 0.6 kb and produced a new sequence at LINE-target junctions. Moreover, our data suggest that L1 retrotransposition can be used to repair double-strand DNA breaks (DSBs). These results imply that L1s have had considerable impact on the evolution of the zebrafish genome.

Animals↗

PubMed2025

Uncovering parental exposure risks of TCPP: Impaired development and metabolic homeostasis in zebrafish offspring.

As brominated flame retardants are phased out, tris (1‑chloro-2-propyl) phosphate (TCPP), a phosphorus-based flame retardant, has emerged as a prominent detectable flame retardant in the environment. However, TCPP has been found to exhibit endocrine-disrupting effects on organisms, raising significant safety concerns. In our study, we utilized the zebrafish model to explore the toxic effects of parental TCPP exposure on offspring and uncover its regulatory mechanisms through metabolomics analysis. Moreover, the impact on the nervous system and lipid metabolism was examined through behavioral analysis and specific staining. Our findings demonstrated that both embryonic and parental TCPP exposure induced developmental disorders in larvae, along with decreased locomotor activity and disordered lipid metabolism homeostasis. Parental exposure to TCPP, exhibiting stronger developmental toxicity than direct embryonic exposure, notably led to reductions in crucial energy substrates such as amino acids and carbohydrates. Meanwhile, embryonic TCPP exposure primarily affected the endogenous lipid-related metabolites including phospholipids, lipid-soluble vitamins, steroids and fatty acids, promoting lipid accumulation in larval liver and subcutaneous tissue. What's more, continuously parental and embryonic exposure showed the most pronounced effects on zebrafish development and metabolic regulation. Our study highlights the risk posed by parental exposure to TCPP on offspring zebrafish, underscoring the need for comprehensive consideration of the impact from parental exposure in pollutants regulation.

Animals↗

PubMed2003

Steps during the development of the zebrafish locomotor network.

This review summarizes recent data from our lab concerning the development of motor activities in the developing zebrafish. The zebrafish is a leading model for studies of vertebrate development because one can obtain a large number of transparent, externally and rapidly developing embryos with motor behaviors that are easy to assess (e.g. for mutagenic screens). The emergence of embryonic motility was studied behaviorally and at the cellular level. The embryonic behaviors appear sequentially and include an early, transient period of spontaneous, alternating tail coilings, followed by responses to touch, and swimming. Patch clamp recording in vivo revealed that an electrically coupled network of a subset of spinal neurons generates spontaneous tail coiling, whereas a chemical (glutamatergic and glycinergic) synaptic drive underlies touch responses and swimming and requires input from the hindbrain. Swimming becomes sustained in larvae once serotonergic neuromodulatory effects are integrated. We end with a brief overview of the genetic tools available for the study of the molecular determinants implicated in locomotor network development in the zebrafish. Combining genetic, behavioral and cellular experimental approaches will advance our understanding of the general principles of locomotor network assembly and function.

Animals↗

PubMed2005

Matrix metalloproteinase expression and function during fin regeneration in zebrafish: analysis of MT1-MMP, MMP2 and TIMP2.

Matrix metalloproteinases (MMPs) play key roles in the turnover of extracellular matrix (ECM) and, thereby, function as key regulators of cell-ECM interactions during development. In spite of their importance during developmental processes, relatively little has been reported about the role of these metalloproteinases during limb development and regeneration. To approach the problem of cell-ECM interactions during limb (fin) regeneration, we have utilized zebrafish as an experimental model. Based on previous MMP cloning studies from our laboratory, the current study has focused on the expression of membrane-type 1 metalloproteinase (MT1-MMP), gelatinase A (MMP-2) and endogenous tissue inhibitor 2 of metalloproteinases (TIMP-2) during fin regeneration in adult zebrafish. In situ analysis indicated co-expression of zmt1-mmp, zmmp-2, and ztimp-2 mRNA transcripts in regenerating caudal fins. In situ gelatin-zymography confirmed the presence of active metalloproteinases in regenerating fins. zmt1-mmp, zmmp-2, and ztimp-2 mRNA transcripts were expressed in the blastema and basal epithelium during caudal fin regeneration while expression of type IV collagen [zcol-IV(a5)] transcripts (a basal lamina component) was restricted to the basal epithelium. Fin outgrowth was greatly reduced in the presence of GM6001 (an inhibitor of MMP activity) indicating the importance of these enzymes during fin regeneration. Previous studies by Itoh (EMBO, 2001) indicated that expression of a vertebrate MT1-MMP construct containing only the hemopexin-transmembrane-cytoplasmic domains (MT1HPX) resulted in blockage of MT1-MMP homophilic complex formation and subsequent inhibition of pro-MMP-2 activation. Interference with homophilic complex formation was attributed to expression of the hemopexin domain at the cell surface. Building upon these earlier findings, the current study found that ectopic expression of MT1HPX in fin regenerates inhibited the regeneration process and resulted in a reduction in cell proliferation in the blastema. Taken together, these results indicate that MMPs have an important role during fin regeneration in zebrafish.

Animals↗

PubMed2004

Identification and characterization of 17 beta-hydroxysteroid dehydrogenases in the zebrafish, Danio rerio.

The 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) are key enzymes in the final steps of steroid hormone synthesis. 17beta-HSD type 1 (HSD17B1) catalyzes the reduction of estrone to estradiol, while type 3 (HSD17B3) performs the conversion of androstenedione to testosterone. Here we present a functional genomics study of putative candidates of these enzymes in the zebrafish. By an in silico screen of zebrafish EST databases we identified three candidate homologs for both HSD17B1 and HSD17B3. Phylogenetic analysis, unique expression patterns (RT-PCR) during embryogenesis and adulthood, as well as activity measurements revealed that one of the HSD17B1 candidates is the zebrafish homolog, while the other two are paralogous photoreceptor-associated retinol dehydrogenases. All three HSD17B3 candidate genes showed nearly identical, ubiquitous expressions in embryogenesis and adult tissues and were identified to be paralogs of HSD17B12 and a yet uncharacterized putative steroid dehydrogenase. Phylogenetic analysis shows that HSD17B3 and HSD17B12 are descendants from a common ancestor.

17-Hydroxysteroid Dehydrogenases↗