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PubMed2006

The zebrafish cornea: structure and development.

PURPOSE: To evaluate the zebrafish as a model for the studies of corneal development and disease. METHODS: Zebrafish embryos and larvae at various stages of development were used for documenting corneal morphogenesis and differentiation. Corneal samples were collected from embryos, larvae, and adult zebrafish for histologic and electron microscopy analysis. Expression patterns of corneal polypeptides were investigated by immunostaining of sections. RESULTS: The zebrafish cornea develops rapidly during embryogenesis, so that its three major layers, the epithelium, the stroma, and the endothelium, are well formed by day 3 postfertilization. The subsequent steps of corneal differentiation, such as the thickening of the corneal stroma, proceed relatively slowly. Several polypeptides are highly enriched in the epithelium or the stroma of the larval and adult zebrafish cornea and are excellent markers of corneal differentiation. CONCLUSIONS: Development and differentiation of the zebrafish cornea are easily accessible to analysis. Anatomic and ultrastructural characterization of the zebrafish cornea demonstrates many similarities to the human cornea and provides the basis for the use of the zebrafish model both to analyze the basic genetic mechanisms of corneal development and to study the causes of corneal disease.

Animals↗
PubMed2004

The chianti zebrafish mutant provides a model for erythroid-specific disruption of transferrin receptor 1.

Iron is a crucial metal for normal development, being required for the production of heme, which is incorporated into cytochromes and hemoglobin. The zebrafish chianti (cia) mutant manifests a hypochromic, microcytic anemia after the onset of embryonic circulation, indicative of a perturbation in red blood cell hemoglobin production. We show that cia encodes tfr1a, which is specifically expressed in the developing blood and requisite only for iron uptake in erythroid precursors. In the process of isolating zebrafish tfr1, we discovered two tfr1-like genes (tfr1a and tfr1b) and a single tfr2 ortholog. Abrogation of tfr1b function using antisense morpholinos revealed that this paralog was dispensable for hemoglobin production in red cells. tfr1b morphants exhibited growth retardation and brain necrosis, similar to the central nervous system defects observed in the Tfr1 null mouse, indicating that tfr1b is probably used by non-erythroid tissues for iron acquisition. Overexpression of mouse Tfr1, mouse Tfr2, and zebrafish tfr1b partially rescued hypochromia in cia embryos, establishing that each of these transferrin receptors are capable of supporting iron uptake for hemoglobin production in vivo. Taken together, these data show that zebrafish tfr1a and tfr1b share biochemical function but have restricted domains of tissue expression, and establish a genetic model to study the specific function of Tfr1 in erythroid cells.

Amino Acid Sequence↗
PubMed2004

Functional genomics tools for the analysis of zebrafish pigment.

Genetic model organisms are increasingly valuable in the post-genomics era to provide a basis for comparative analysis of the human genome. For higher order processes of vertebrate pigment cell biology and development, the mouse has historically been the model of choice. A complementary organism, the zebrafish (Danio rerio), shares many of the signaling and biological processes of vertebrates, e.g. neural crest development. The zebrafish has a number of characteristics that make it an especially valuable model for the study of pigment cell biology and disease. Large-scale genetic screens have identified a collection of pigmentation mutants that have already made valuable contributions to pigment research. An increasing repertoire of genomic resources such as an expressed sequence tag-based Gene Index (The Institute for Genomic Research) and improving methods of mutagenesis, transgenesis, and gene targeting make zebrafish a particularly attractive model. Morpholino phosphorodiamidate oligonucleotide (MO) 'knockdown' of pigment gene expression provides a non-conventional antisense tool for the analysis of genes involved in pigment cell biology and disease. In addition, an ongoing, reverse-genetic, MO-based screen for the rapid identification of gene function promises to be a valuable complement to other high-throughput microarray and proteomic approaches for understanding pigment cell biology. Novel reagents for zebrafish transgenesis, such as the Sleeping Beauty transposon system, continue to improve the capacity for genetic analysis in this system and ensure that the zebrafish will be a valuable genetic model for understanding a variety of biological processes and human diseases for years to come.

Animals↗
PubMed2004

Development of cell cultures with competency for contributing to the zebrafish germ line.

The zebrafish is an established model for the genetic analysis of vertebrate development. Forward-genetic screens have generated thousands of mutations, and antisense-based methods have been used to transiently knockdown gene expression during embryogenesis. Although these methods have made the zebrafish a valuable system for the identification and functional characterization of developmentally important genes, one deficiency of the zebrafish model is the absence of methods to introduce targeted mutations to generate knockout lines of fish. Application of gene-targeting methods has been limited in nonmurine species due to the absence of germ-line competent embryonic stem (ES) cell lines. Recently, progress was made in addressing this problem by the derivation of zebrafish embryo cell lines that remain pluripotent and germ-line competent for multiple passages in culture. Zebrafish germ-line chimeras were generated using cultures derived from embryos at two different developmental stages, and targeted insertion of vector DNA by homologous recombination was demonstrated in both cultures. Several strategies are being used to optimize the production and identification of germ-line chimeras. The zebrafish embryo cell culture system should provide the basis of a gene-targeting approach that will complement other genetic strategies and improve the utility of the zebrafish model for studies of development and disease.

Animals↗
PubMed2006

Zebrafish and medaka as models for bone research including implications regarding space-related issues.

Teleost fish develop bones directly from mesenchymal condensations and from cartilage precursors. At the cellular level, the involved cell populations share many features with their mammalian counterparts. In addition, several genes are already described in fish showing high homology in amino acid sequence and expression with the corresponding genes of tetrapods that are involved in bone metabolism. Therefore, analysis of the underlying molecular mechanism in fish, in particular zebrafish and medaka, will increase the knowledge in teleosts. Furthermore, it will help to identify novel genes and regulatory pathways of bone homeostasis and skeletal disorders also in higher vertebrates, including disorders caused by altered gravity.

Adaptation, Physiological↗
PubMed2006

Zebrafish (Danio rerio) as a model for the study of vaccination against viral haemorrhagic septicemia virus (VHSV).

The rhabdovirus viral haemorrhagic septicemia virus (VHSV) is the etiological agent of one of the most important salmonid viral diseases. In the present work, the ability of VHSV to infect and replicate in zebrafish at low temperature (15 degrees C) was demonstrated. Zebrafish was also used to determine the effectiveness of the recombinant virus rIHNV-Gvhsv GFP as a live attenuated vaccine against the virulent VHSV strain. Fish intraperitoneally injected with 3 x 10(6) to 3 x 10(5)TCID50/ml of the wild type VHSV showed a 100% of cumulative mortality, meanwhile only 57% of mortality was obtained in bath infections. Infected fish showed external clinical signs and histological observations revealed the appearance of small haemorrhages in the muscle, kidney, liver and dermis. Neither mortalities nor clinical signs were recorded in fish infected with a live attenuated recombinant virus. By RT-PCR technique, VHSV was detected in all the organs as early as 24h, but the recombinant virus was not detected in all the sampled days. VHSV was able to replicate "in vitro" in head kidney cells but the replication capacity of the attenuated viral strain was limited. The recombinant virus rIHNV-Gvhsv GFP was able to protect against VHSV with a survival rate ranging from 20% to 60% depending of the vaccine dose. The increase of TLR3, IFNalphabeta, Mx, IFNgamma and TNFalpha expression at 72h post-infection in the kidney of VHSV-infected fish contrasted with the results obtained with the avirulent virus, which did not induce an increment of this expression in infected fish. Zebrafish is a suitable animal model to study VHSV infection and immune (innate and adaptive) responses and, more importantly, we demonstrate for the first time the usefulness of the zebrafish as a vaccination model to viral diseases. In addition, the high protection obtained with the live attenuated virus demonstrates that the zebrafish is able to mount an efficient antiviral immune response at 15 degrees C.

Animals↗
PubMed2005

Large-scale screen highlights the importance of capsule for virulence in the zoonotic pathogen Streptococcus iniae.

Zoonotic pathogens have the unique ability to cross the species barrier, causing disease in both humans and specific animal hosts. Streptococcus iniae is a zoonotic pathogen of both fish and humans, and the clinical presentations of S. iniae infections in fish and humans are very similar to those caused by various human-specific streptococcal pathogens. Virulence mechanisms required for infection by this pathogen of either host have yet to be determined. Using the previously reported zebrafish infectious disease model, we performed a large-scale screening to determine genes required for systemic infection. Screening 1,128 signature-tagged transposon mutants through the zebrafish model allowed identification of 41 potential mutants that were unable to survive within the host environment. Greater than 50% of the mutants that could be identified through homology searches were highly homologous to genes found in other human-specific streptococcal pathogens, while 32% were found to have no homology to any sequences found in the databases, suggesting as yet unknown gram-positive bacterial virulence factors. A large percentage of the insertions were found to be located in several putative capsule synthesis genes, an important virulence component for other systemic pathogens. Density gradient assays demonstrated that several of these putative capsule mutants have dissimilar buoyant densities, suggesting different levels of capsule synthesis. Putative capsule mutants were also less resistant to phagocytosis in whole-blood assays than wild-type S. iniae. Our initial large-scale characterization of S. iniae virulence highlights the importance of the capsule for successful infection.

Animals↗
PubMed2006

her5 expression reveals a pool of neural stem cells in the adult zebrafish midbrain.

Current models of vertebrate adult neural stem cells are largely restricted to the rodent forebrain. To extract the general mechanisms of neural stem cell biology, we sought to identify new adult stem cell populations, in other model systems and/or brain areas. The teleost zebrafish appears to be an ideal system, as cell proliferation in the adult zebrafish brain is found in many more niches than in the mammalian brain. As a starting point towards identifying stem cell populations in this system, we used an embryonic neural stem cell marker, the E(spl) bHLH transcription factor Her5. We demonstrate that her5 expression is not restricted to embryonic neural progenitors, but also defines in the adult zebrafish brain a new proliferation zone at the junction between the mid- and hindbrain. We show that adult her5-expressing cells proliferate slowly, self-renew and express neural stem cell markers. Finally, using in vivo lineage tracing in her5:gfp transgenic animals, we demonstrate that the her5-positive population is multipotent, giving rise in situ to differentiated neurons and glia that populate the basal midbrain. Our findings conclusively identify a new population of adult neural stem cells, as well as their fate and their endogenous environment, in the intact vertebrate brain. This cell population, located outside the forebrain, provides a powerful model to assess the general mechanisms of vertebrate neural stem cell biology. In addition, the first transcription factor characteristic of this cell population, Her5, points to the E(Spl) as a promising family of candidate adult neural stem cell regulators.

Animals↗
PubMed1997

Heat shock protein gene expression during embryonic development of the zebrafish.

Heat shock genes exhibit complex patterns of spatial and temporal regulation during embryonic development of a wide range of organisms. Our laboratory has been involved in an analysis of heat shock gene expression in the zebrafish, a model system which is now utilized extensively for the examination of early embryonic development of vertebrates. Members of the zebrafish hsp47, hsp70 and hsp90 gene families have been cloned and shown to be closely related to their counterparts in higher vertebrates. Expression of these genes has been examined using Northern blot and whole mount in situ hybridization analyses. Both the hsp47 and hsp90 genes are expressed in a highly tissue-restricted manner during normal development. The data raise a number of interesting questions regarding the function and regulation of these heat shock genes during early zebrafish development.

Animals↗
PubMed2005

Paired motor neuron-muscle recordings in zebrafish test the receptor blockade model for shaping synaptic current.

The transparent spinal cord and electrically compact fast muscle of zebrafish offer the first opportunity to perform simultaneous whole-cell patch-clamp recordings from both motor neuron and target skeletal muscle in situ. Our paired recordings reveal the fastest reported kinetics for both spontaneous and evoked synaptic currents at any synapse and a large quantal size that facilitates the resolution of spontaneous synaptic currents. We used this preparation to test the recent proposal that open channel block of the acetylcholine receptor by acetylcholine modulates the kinetics and timing of transmission between nerve and muscle in larval zebrafish (Legendre et al., 2000). Contrary to the predictions of this model, we find similar delay and onset kinetics of synaptic current at positive and negative muscle membrane potentials, even after inhibition of acetylcholinesterase. In contrast, blockade of motor neuron K channels by 4-aminopyridine prolonged the action potential and introduced a significant delay and slowing of evoked synaptic currents, demonstrating our ability to measured altered transmitter release with this system. We conclude that the kinetics of neuromuscular synaptic currents in zebrafish is not governed by receptor block.

Acetylcholine↗
PubMed2006

Oculomotor instabilities in zebrafish mutant belladonna: a behavioral model for congenital nystagmus caused by axonal misrouting.

A large fraction of homozygous zebrafish mutant belladonna (bel) larvae display a reversed optokinetic response (OKR) that correlates with failure of the retinal ganglion cells to cross the midline and form the optic chiasm. Some of these achiasmatic mutants display strong spontaneous eye oscillations (SOs) in the absence of motion in the surround. The presentation of a stationary grating was necessary and sufficient to evoke SO. Both OKR reversal and SO depend on vision and are contrast sensitive. We built a quantitative model derived from bel fwd (forward) eye behaviors. To mimic the achiasmatic condition, we reversed the sign of the retinal slip velocity in the model, thereby successfully reproducing both reversed OKR and SO. On the basis of the OKR data, and with the support of the quantitative model, we hypothesize that the reversed OKR and the SO can be completely attributed to RGC misrouting. The strong resemblance between the SO and congenital nystagmus (CN) seen in humans with defective retinotectal projections implies that CN, of so far unknown etiology, may be directly caused by a projection defect.

Animals↗
PubMed2006

Zebrafish as a powerful vertebrate model system for in vivo studies of cell death.

Understanding and manipulating cell death pathways are critical to our ability to treat human degenerative diseases and cancer. The zebrafish Danio rerio, a common aquatic pet, has evolved as a powerful tool for the discovery of genes regulating cellular suicide both during normal vertebrate development and after genetic or environmental insult. In this review, we describe the techniques that can be applied to studying cell death in zebrafish as well as highlighting what has been discovered so far. Finally, we discuss future perspectives in the field and how they relate to human disease.

Animals↗
PubMed2004

A relational-tubular (ReTu) deformable model for vasculature quantification of zebrafish embryo from microangiography image series.

Embryonic cardiovascular system plays a vital role in embryonic development of human and animal. In this work, we introduce a novel deformable model, which we called Relational-tubular (ReTu) deformable model for segmenting and quantifying the embryonic vasculature of zebrafish embryo from microangiography image series. Particularly, to incorporate additional constraints on the spatial relationships among vessel branches, we introduce a new energy term called relation energy into the model energy function. This energy item acts as a repulsion force between neighboring vessels during the deformation to encourage them to move towards their respective volume data. Using the ReTu deformable model, the deformation process is an iterative two-stage procedure: vascular axis deformation and vascular surface deformation. The efficiency and robustness of this approach are demonstrated by experiments which show that satisfactory quantifications of the vasculature can be obtained after 3-4 iterations.

Angiography↗
PubMed2006

Thioacetamide induced liver damage in zebrafish embryo as a disease model for steatohepatitis.

Steatohepatitis has recently been increasing as a cofactor influencing the progression of fibrosis, cirrhosis, adenoma and carcinoma in liver; however, the mechanisms by which it contributes to liver injury remain uncertain. We induced steatohepatitis in zebrafish embryos using thioacetamide (TAA). TUNEL assay revealed significant increasing of apoptosis in liver after 5 days post fertilization and the increasing of apoptosis was observed to be associated with the up-regulation of apoptotic genes such as, bad, bax, P-38a, caspase-3 and 8, and JNK-1. Histological sections by oil red O stain showed the accumulation of fatty droplets which causes the pushing of the nucleus towards one side. Up-regulation of steatosis markers such as, ACC, adiponectin, PTL, CEBP- alpha and beta, SREBP-1 was also observed. Furthermore, the elevation of glutathione peroxidase in TAA treated embryos indicated that TAA induces lipid peroxidation which leads to causes liver damage. Zebrafish has already been considered as a good human disease model and in this context; TAA-treated zebrafish may serve as a good animal model to study the molecular pathogenesis of steatohepatitis. Moreover, non-availability of specific drugs to prevent steatohepatitis, this animal model may serve as a powerful preclinical platform to study the therapeutic strategies and for evaluating chemoprevention strategies for this disease.

Animals↗
PubMed2007

Hallucinatory and rewarding effect of salvinorin A in zebrafish: kappa-opioid and CB1-cannabinoid receptor involvement.

RATIONALE: The hallucinatory effect and potential abuse of salvinorin A, the major ingredient of Salvia divinorum, has not been documented in animals. OBJECTIVE: The effects of salvinorin A on the zebrafish (Danio rerio) model, through its swimming behavior and conditioned place preference (CPP) task, was studied. MATERIALS AND METHODS: Swimming activity was determined in a squared observational chamber after an i.m. treatment of salvinorin A (0.1-10 microg/kg). For the CPP test, zebrafish were given salvinorin A (0.2 and 1 microg/kg) or vehicle and evaluated in a two-compartment chamber. RESULTS: Salvinorin A (0.1 and 0.2 microg/kg) induced accelerated swimming behavior in comparison with vehicle, whereas a "trance-like" effect, at doses as 5 and 10 microg/kg, was obtained. Pretreatment with the kappa-opioid antagonist, nor-binaltorphimine (nor-BNI; 10 mg/kg) and the cannabinoid type 1 (CB(1)) antagonist, rimonabant (1 mg/kg), blocked salvinorin A-induced both stimulating and depressive effects obtained at a dose of 0.2 and 10 microg/kg, respectively. In the CPP test, salvinorin A (0.2 and 0.5 microg/kg) produced an increase in the time spent in the drug-associated compartment. A dose of 1 microg/kg produced no effect, whereas a dose of 80 microg/kg induced aversion. Pretreatment with nor-BNI or rimonabant fully reversed the reinforcing properties of salvinorin A (0.5 microg/kg). CONCLUSIONS: Taken together, these results indicate that salvinorin A, as is sometimes reported in humans, exhibits rewarding effects, independently from its motor activity, suggesting the usefulness of the zebrafish model to study addictive behavior. These effects appear mediated by activation of both kappa-opioid and cannabinoid CB(1) receptors.

Animals↗