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PubMed1998

Mutant rescue by BAC clone injection in zebrafish.

Genes essential for vertebrate body plan specification, organ development, and organ function are likely to be shared between mammals and zebrafish, but only in zebrafish have large-scale, genome-wide mutagenesis screens been conducted to isolate embryonic lethal mutations. Discovering the roles played by these disrupted genes requires their molecular characterization, which would be facilitated by assaying large cloned genomic DNAs for their potential to rescue mutant phenotypes. Here we demonstrate that bacterial artificial chromosomes can rescue the phenotype of floating head (flh) mutants. Homozygous flh embryos lack a differentiated notochord and have a reduced, discontinuous floor plate. Mutant embryos injected with genomic clones containing the flh+ gene often had stretches of several to many notochord cells overlaid by a row of floor-plate cells. In contrast, control mutant embryos injected with artificial chromosomes lacking the flh+ gene failed to form notochord. We conclude that the injection of large-insert genomic clones will speed the isolation of zebrafish genes disrupted by mutation and hence the identification of gene functions necessary for development of vertebrate embryos.

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PubMed1995

A novel gene expressed during zebrafish gastrulation identified by differential RNA display.

Vertebrate gastrulation is a dynamic period of development characterized by extensive cell migrations. This stage of development is likely to require the expression of a new genetic repertoire to initiate and direct these dramatic changes. The differential RNA display has been used to identify genes specifically expressed during the gastrula stage of a model vertebrate, the zebrafish. One of the genes isolated by the differential display technique has been sequenced and characterized for its spatial and temporal expression. This gene, called G12, is expressed during a narrow window of time during gastrulation and is restricted to a single cell type. At this time of development the zebrafish embryo consists of three cell types: the yolk cell, EVL cells and deep cells. Interestingly, both EVL and deep cells derive early in development from common progenitor cells but G12 expression is restricted only to the EVL lineage. Comparison of the amino acid sequence from this gene with the Genbank database indicates similarity to two previously reported mammalian genes. The similarity between these three genes suggests that they may serve a common function. The G12 gene is the first example of restricted gene expression in EVL cells of the zebrafish. The G12 gene should prove to be a useful model for the study of regulated gene expression during gastrulation.

Amino Acid Sequence↗

PubMed2004

p63 and epithelial appendage development.

Abstract Epithelial appendages share a common developmental program that relies on extensive interactions between epithelia and adjacent mesenchyme. The transcription factor p63 has a critical role in epithelial appendage development in both vertebrates and non-vertebrates. Both mice and zebrafish lacking p63 expression fail to develop epithelial appendages and other structures that develop as a result of epithelial-mesenchymal interactions. Furthermore, dominantly inherited mutations in p63 are the cause of a subset of human ectodermal dysplasias, which are characterized by developmental abnormalities in epithelia and epithelial appendages. While the importance of p63 for epithelial appendage development is evident, the molecular mechanisms by which p63 functions are largely unknown. In this review, we will discuss the current knowledge of the developmental role of p63 and the implications for epithelial appendage development.

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PubMed1998

Isolation of the zebrafish homologues for the tie-1 and tie-2 endothelium-specific receptor tyrosine kinases.

Several characteristics of the zebrafish embryo make it an attractive model in which to study the development of the cardiovascular system. The utility of the zebrafish as a model of mammalian vascular development will depend on the conservation of molecular and morphogenetic mechanisms of vessel growth. Here, we report the cloning of the zebrafish homologues of the endothelium-specific receptor tyrosine kinases tie-1 and tie-2. The Z tie-2 clone represents the first report of a full-length zebrafish endothelium-specific gene. The zebrafish tie family members have significant structural homology with their murine and human counterparts. In addition, like the murine tie-1 and tie-2 genes, expression was found predominantly in endothelial cells. At 24-hr postfertilization (HPF), Z tie-1 was expressed in all observed populations of endothelial cells. Interestingly, Z tie-2 exhibited a similar, although slightly more restricted, expression pattern. Taken together, these data strongly suggest that mechanisms of vascular development are highly conserved across species and that zebrafish will continue to be a useful model for the investigation of vertebrate embryonic vascular development.

Amino Acid Sequence↗

PubMed2006

Genomewide expression profiling in the zebrafish embryo identifies target genes regulated by Hedgehog signaling during vertebrate development.

Hedgehog proteins play critical roles in organizing the embryonic development of animals, largely through modulation of target gene expression. Little is currently known, however, about the kinds and numbers of genes whose expression is controlled, directly or indirectly, by Hedgehog activity. Using techniques to globally repress or activate Hedgehog signaling in zebrafish embryos followed by microarray-based expression profiling, we have discovered a cohort of genes whose expression responds significantly to loss or gain of Hedgehog function. We have confirmed the Hedgehog responsiveness of a representative set of these genes with whole-mount in situ hybridization as well as real time PCR. In addition, we show that the consensus Gli-binding motif is enriched within the putative regulatory elements of a sizeable proportion of genes that showed positive regulation in our assay, indicating that their expression is directly induced by Hedgehog. Finally, we provide evidence that the Hedgehog-dependent spatially restricted transcription of one such gene, nkx2.9, is indeed mediated by Gli1 through a single Gli recognition site located within an evolutionarily conserved enhancer fragment. Taken together, this study represents the first comprehensive survey of target genes regulated by the Hedgehog pathway during vertebrate development. Our data also demonstrate for the first time the functionality of the Gli-binding motif in the control of Hedgehog signaling-induced gene expression in the zebrafish embryo.

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PubMed2000

Patterning the cranial neural crest: hindbrain segmentation and Hox gene plasticity.

Understanding the patterning mechanisms that control head development--particularly the neural crest and its contribution to bones, nerves and connective tissue--is an important problem, as craniofacial anomalies account for one-third of all human congenital defects. Classical models for craniofacial patterning argue that the morphogenic program and Hox gene identity of the neural crest is pre-patterned, carrying positional information acquired in the hindbrain to the peripheral nervous system and the branchial arches. Recently, however, plasticity of Hox gene expression has been observed in the hindbrain and cranial neural crest of chick, mouse and zebrafish embryos. Hence, craniofacial development is not dependent on neural crest prepatterning, but is regulated by a more complex integration of cell and tissue interactions.

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PubMed2003

Two tcf3 genes cooperate to pattern the zebrafish brain.

Caudalizing factors operate in the context of Wnt/beta-catenin signaling to induce gene expression in discrete compartments along the rostral-caudal axis of the developing vertebrate nervous system. In zebrafish, basal repression of caudal genes is achieved through the function of Headless (Hdl), a Tcf3 homolog. In this study, we show that a second Tcf3 homolog, Tcf3b, limits caudalization caused by loss of Hdl function and although this Lef/Tcf family member can rescue hdl mutants, Lef1 cannot. Wnts can antagonize repression mediated by Tcf3 and this derepression is dependent on a Tcf3 beta-catenin binding domain. Systematic changes in gene expression caused by reduced Tcf3 function help predict the shape of a caudalizing activity gradient that defines compartments along the rostral-caudal axis. In addition, Tcf3b has a second and unique role in the morphogenesis of rhombomere boundaries, indicating that it controls multiple aspects of brain development.

Amino Acid Sequence↗

PubMed1999

Growth control in the ontogenetic and regenerating zebrafish fin.

The growth and regeneration of the zebrafish fin provide yet another opportunity to exploit genetics to study important vertebrate problems. Mutants have been identified in zebrafish that affect the development of the embryonic fin, disrupt the normal growth relationship of fin and body, or disrupt the regeneration of the fin. Analysis of a regeneration mutation suggests that the developmental checkpoints that ensure developmental integrity in normal growth are absent in the early stages of regeneration. These stages correspond to the only time in fish developmental when differentiated bone cells divide.

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PubMed1999

Reissner's substance expressed as a transient pattern in vertebrate floor plate.

The function of the floor plate in dorso-ventral patterning of the developing nervous system and in the guidance of commissural axons is well established. However, several morphological aspects concerning the exact localization of its rostral and caudal end and the regional and temporal specialization are still controversial. We present new insights revealed by the expression of Reissner's substance in the floor plate during early neurogenesis of zebrafish, Xenopus, chick and rat. We used a polyclonal antiserum raised against Reissner's substance, which is a secretory product of radial glia in the roof plate of the adult vertebrate brain. In early embryonic stages the rostral boundary of floor plate immunoreaction vary in the different vertebrates. Immunoreactive cells are not only present in the epichordal region (rat) but also in prechordal areas of the midbrain (chick) and forebrain (zebrafish and Xenopus). During further development, Reissner's substance expression disappears first in the most rostral areas and later also in the spinal cord. However, immunopositive labelling in the isthmus region at the mes-metencephalic boundary, described originally as the flexural organ, is most extensive and detectable during a long period of embryonic development. It is proposed that the gradual restriction of Reissner's substance expression to the isthmus reflects the complex differentiation processes in this region also in later embryonic development. Furthermore, the expression pattern in zebrafish indicates that Reissner's substance could play a role in axonal decussation.

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PubMed2003

Susceptibility of zebrafish (Danio rerio) to a model pathogen, spring viremia of carp virus.

To improve our understanding of the genetic basis of fish disease, we developed a pathogen model, using zebrafish (Danio rerio) and spring virema of carp virus (SVCV). Replicate groups of 10 fish were acclimated to 20 or 24 degrees C, then were exposed to SVCV concentrations of 10(3) to 10(5) plaque-forming units per milliliter (PFU/ml) of water and observed daily. In a second trial, fish were acclimated to 15 degrees C, and replicate groups of 10 fish were exposed to SVCV at a concentration of 10(5) PFU/ml; however, the temperature was raised 1 degrees C/wk. Moribund fish were collected for histologic examination, and dead fish were assayed for virus by use of cell culture and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Mortality exceeded 50% in fish exposed to 10(5) PFU of SVCV/ml at the lower temperatures. Clinical signs of disease became evident seven days after viral exposure and were observed most consistently in fish of the 10(5) PFU/ml groups. Affected zebrafish were anorectic and listless, with epidermal petechial hemorrhages followed by death. Use of plaque assays and RT-PCR analysis confirmed presence of SVCV at titers > or = 10(4) PFU/g of tissue. Histologic lesions included multifocal brachial necrosis and melanomacrophage proliferation in gills, liver, and kidneys. These results indicate that zebrafish are susceptible to infection by SVCV under conditions that mimic a natural route of exposure.

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PubMed2003

Zebrafish pronephros: a model for understanding cystic kidney disease.

The embryonic kidney of the zebrafish is the pronephros. The ease of genetic analysis and experimentation in zebrafish, coupled with the simplicity of the pronephros, make the zebrafish an ideal model system for studying kidney development and function. Several mutations have been isolated in zebrafish genetic screens that result in cyst formation in the pronephros. Cloning and characterization of these mutations will provide insight into kidney development but may also provide understanding of the molecular basis of cystic kidney diseases. In this review, we focus on the zebrafish as a model for understanding cystic kidney disease and the links between cystic kidney disease and left-right patterning.

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PubMed2005

Secondary neurogenesis in the brain of the African clawed frog, Xenopus laevis, as revealed by PCNA, Delta-1, Neurogenin-related-1, and NeuroD expression.

After primary neurogenesis in the Xenopus laevis embryo, a massive new surge of neurogenesis and related neurogenic and proneural gene expression occurs in the spinal cord at the beginning of the larval period (starting at Stage 46), which corresponds to well-documented secondary neurogenesis in larval zebrafish central nervous system development. Here, we document related neural proliferation and gene expression patterns in the brain of Xenopus, in various embryonic and larval stages, showing the distribution of proliferative cells (immunostaining of cells containing the proliferating cell nuclear antigen; the auxiliary protein of DNA polymerase delta; PCNA), and the activity of some critical genes expressed during neurogenesis (i.e., Delta-1, Neurogenin-related-1, NeuroD). This study reveals that the early larval stage in Xenopus (Stage 48) displays patterns of proliferation (PCNA), as well as of neurogenic (Delta-1) and proneural (Ngnr-1; NeuroD) gene expression that are qualitatively almost identical to those seen in the 3-day postembryonic zebrafish or the 12.5/13.5-day embryonic mouse. Furthermore, a comparable bauplan of early proliferation zones (including their neuromeric organization) as described in the postembryonic zebrafish apparently exists in tetrapods (Xenopus). Altogether, the data presented suggest a common brain bauplan on the level of early proliferation patterns and neurogenic/proneural gene activity in anamniotes, if not vertebrates.

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PubMed2006

Dynamic expression patterns of zebrafish 1G5 (1G5z), a calmodulin kinase-like gene in the developing nervous system.

Evolutionarily well-conserved Ca(2+)/calmodulin-dependent protein kinase (CaMK) proteins are known for their role as Ca(2+) signaling mediators. 1G5 encodes a CaMK like protein, which belongs to a calmodulin (CaM) kinase gene family. Here, we report the isolation of zebrafish homologue of mammalian 1G5, which we named 1G5z. 1G5z is composed of three major domains: (1) an N-terminal serine/threonine kinase domain, (2) a central calmodulin-binding domain, and (3) a C-terminal alanine-rich domain, the 1G5z-specific domain. 1G5z shares 83 approximately 84% homology with other vertebrate 1G5 proteins. Spatiotemporal expression studies found that 1G5z is expressed by means of zygotic transcription and appears in various neuronal tissues from the 20-somite stage. 1G5z transcripts are more regionalized in the brain and spinal cord at 24 hr postfertilization (hpf). At 35 hpf, 1G5z transcripts are exclusively present in the anterior trunk spinal cord as well as in the hindbrain, tegmentum, hypothalamus, and telencephalon. This expression pattern lasts until 48 hpf but ceases in the trunk. At 72 hpf, 1G5z is abundantly transcribed particularly in the specific region of the tectum and eye. We further observed that the number of 1G5z-positive cells is dramatically increased in the mindbomb mutant embryos but abolished in the trigeminal ganglion and caudal trunk sensory neuron of the neurogenin1 morphant at 24 hpf. In addition, bromodeoxyuridine staining further confirmed that the 1G5z-positive cells were postmitotic sensory and interneurons.

Amino Acid Sequence↗

PubMed1996

Detection of neuron-specific protein gene product (PGP) 9.5 in the rat and zebrafish using anti-human PGP9.5 antibodies.

Protein gene product (PGP) 9.5 is a developmentally regulated neuron- and neuroendocrine cell-specific ubiquitin carboxy-terminal hydrolase (UCHL1) expressed throughout the mammalian central and peripheral nervous systems. We have compared the use of monoclonal and polyclonal antibodies raised against human PGP9.5 for immunodetection of the protein in tissues of the zebrafish and rat. We show that a monoclonal antibody 13C4, which recognises an N-terminal epitope, detects PGP9.5 on Western blots as a single 27 kDa band present at high levels in zebrafish and rat brain. By contrast, the polyclonal antisera recognises multiple tissue-specific proteins in the rat and fails to detect PGP9.5 in the zebrafish. Finally, we have developed a specific ELISA assay for detection of cellular PGP9.5 using MAb13C4 and have employed the assay to show that PGP9.5 is not upregulated during nerve growth factor (NGF)-induced differentiation of rat PC12 cells.

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PubMed2001

Development of an ELISA for vitellogenin in whole body homogenate of zebrafish (Danio rerio).

The yolk protein, lipovitellin (Lv) was purified from ovaries of mature female zebrafish (Danio rerio) by gel filtration and anion exchange chromatography. Polyclonal antibodies against Lv were raised in rabbits. Anti-Lv IgG was purified by affinity chromatography. SDS-PAGE followed by Western blotting was performed to analyse the specificity of the antibody and the immunological similarities between Lv and vitellogenin (Vtg). Anti-Lv IgG was used to develop a direct non-competitive sandwich ELISA to measure Vtg concentrations of whole body homogenate (WBH) in zebrafish. The intra- and interassay variabilities were 5.8% and 10.4%, respectively. The sensitivity was 0.2 ng Vtg x ml(-1) and the practical detection limit was 40 ng Vtg x g(-1) fish (wet weight). Adult male zebrafish were exposed to a nominal water concentration of 10 ng x l(-1) of ethinylestradiol (EE2) in a semi-static exposure system for 7 days. Compared with the control group, exposure to 10 ng EE2 x l(-1) induced a 200-fold increase in Vtg levels.

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PubMed1990

Axonogenesis in the brain of zebrafish embryos.

We analyzed the pattern and development of the earliest tracts and followed pathfinding by the growth cones of an identified cluster of neurons in the brain of zebrafish embryos. Neurons were labeled with an antibody which labels many embryonic neurons, a lipophilic axonal tracer dye, and intracellular dye injections. The embryonic brain is extremely simple, and at 28 hr of development, the forebrain and midbrain consist of 8 main axonal tracts which are arranged as a set of longitudinal tracts connected by commissures. Each tract is established by identified clusters of approximately 2-12 neurons found in discrete regions of the brain. Many identified clusters of neurons project axons in a defined direction appropriate for the cluster and have axons with stereotyped trajectories, suggesting that their growth cones follow cell-specific routes. This was confirmed with intracellular dye injections for neurons of the nucleus of the posterior commissure. The growth cones of these neurons arrive at a site in the anterior tegmentum where 4 tracts meet. At this site, they could, in principle, turn in a number of directions but always extend posteriorly into one of the tracts. The pattern of pathfinding by these growth cones suggests the testable hypothesis that the growth cones of identified clusters of neurons establish the simple set of early tracts by selecting cluster-specific pathways at such intersections in order to reach their targets in the brain.

Acetylation↗

PubMed2026

Zebrafish as a Model Organism to Study Neurotoxicity: A Potential Tool for Neuroprotective Drug Discovery.

INTRODUCTION: Danio rerio, the zebrafish, serves as an excellent model in neuroprotective drug discovery due to its conserved nervous system organization, neurotransmitter pathways, antioxidant defenses, and genomic similarity to mammals. METHODS: A systematic literature search following PRISMA 2020 guidelines was conducted across Pub- Med, Scopus, Web of Science, and Google Scholar. Studies published between 2020 and 2025 were prioritized, with earlier key papers included for context. The data on larval, adult, and genetically modified zebrafish models were analyzed for neurotoxic effects, focusing on study design, toxicants, and neurobehavioral or molecular outcomes. RESULTS: Neurotoxicants such as chlorpyrifos, bisphenol, triphenyl phosphate, aluminum, ammonium acetate, arsenic, zinc, acrylamide, methylmercury, and tris (1,3-dichloro-2-propyl) phosphate were shown to cross the zebrafish blood-brain barrier. These exposures caused significant behavioral alterations, neurotransmitter imbalances, oxidative stress, and gene or protein expression changes related to brain function. Analysis of the transgenic zebrafish revealed notable alterations in neuronal development and axonal morphology upon exposure to various neurotoxic chemicals. DISCUSSION: Zebrafish display neurotoxic responses with a close resemblance to mammals, supporting their translational value in neurotoxicity and drug discovery studies. However, limitations such as a less complex brain compared to mammals, quick neuronal regeneration, limited tissue access, and difficulties in drug absorption quantification warrant refinements in zebrafish models. CONCLUSION: Zebrafish offer a versatile, cost-effective, and genetically tractable system for neurotoxicity and neuroprotection research. This systematic review highlights their crucial role in neuroprotective drug discovery while emphasizing the need for improved methodological approaches to enhance translational reliability.

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PubMed2000

Different regulatory elements are necessary for alpha1 tubulin induction during CNS development and regeneration.

Developing and regenerating neurons induce genes whose products are necessary for axonal growth, such as that encoding alpha1 tubulin. To determine whether alpha1 tubulin gene induction uses similar mechanisms during CNS development and regeneration, we compared wild-type and mutant alpha1 tubulin promoter activity in the developing and regenerating CNS of transgenic zebrafish. Wild-type alpha1 tubulin promoter activity increased dramatically in the developing and regenerating CNS. In contrast, we generated a mutation in the alpha1 tubulin promoter that prevented its increase during development but retained regeneration-dependent induction in the adult. These results suggest that at least some of the signaling mechanisms used to activate alpha1 tubulin promoter activity during CNS regeneration are different from those used to activate this promoter during development.

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