On Herrera and Jagadeeswaran's "Annual fish as a genetic model for aging".
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Genetic models in pathogenesis.
To decipher the complexity of host-pathogen interactions the widest possible range of model hosts and of analytical methods is required. As some virulence mechanisms and certain host responses have been conserved throughout evolution, even simple organisms can be used as model hosts to help our understanding of infectious diseases. The availability of molecular genetic tools and a cooperative community of researchers are pivotal to the emergence of model systems. In this review, we first summarize the genetic screens that can be used to identify pathogen virulence factors, then we present a comparative overview of existing or emerging genetically tractable host models.
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Animal models.
Research on basic mechanisms that regulate pancreatic organogenesis may help to define molecular pathways involved in the development of pancreatic diseases. In this regard, animal models have become an essential part of advancing our research efforts. There are several animal models which have been utilized specifically for normal pancreatic development and disease pathobiology. Here we highlight some important websites that serve as valuable resources for research in model organisms. In particular, websites containing information on mouse, rat, swine, zebra fish and xenopus models will be discussed due to their direct utility in pancreatic research.
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Duplicate zebrafish pth genes are expressed along the lateral line and in the central nervous system during embryogenesis.
PTH plays a critical role in calcium metabolism in tetrapods. The primary site of PTH expression is the parathyroid glands, although it is also detected in the thymus and hypothalamus. Fish lack anatomically distinct parathyroid glands, and the first animals to evolve parathyroid glands were the amphibians. However, fish do have PTH family ligands and receptors, which are functionally similar to their mammalian counterparts. We report the expression patterns of duplicate zebrafish pth genes during embryogenesis. Both zebrafish pth1 and pth2 transcripts are expressed along the lateral line before the migration of the lateral line primordium and later in development Pth protein is detected in lateral line neuromasts by immunohistochemistry. pth1 transcripts are also detected in the central nervous system in the ventral neural tube. These temporally and anatomically restricted expression patterns imply a novel role for PTH family hormones during embryonic development of the zebrafish and allow for the genetic dissection of PTH function in this model organism.
Afferent Pathways↗
A center of a different stripe.
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Overview: nonmammalian organisms for studies of kidney development and disease.
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Hedgehogs as negative regulators of the cell cycle.
During the development of multicellular animals, cell proliferation must be precisely controlled, as deregulated proliferation can lead to overgrowth and cancer. In addition, proliferation must be tightly integrated with pattern formation and differentiation to generate the required number of cells in the right organs, and at the right time. All major signaling pathways employed during embryogenesis have been implicated in cell cycle regulation, indicating that no single pathway has been dedicated to this task. Also, the precise role of a particular signaling pathway in regulating proliferation is highly dependent on the cellular context, and may have opposite effects on cell cycle progression in different cells and tissues. The Hedgehog (Hh) family of signaling proteins is known to control both differentiation and proliferation during development. So far, studies addressing the effect of Hh signaling on proliferation have shown it to have a stimulatory effect on cell cycle progression. Here we review several recent studies indicating that Hh signaling can also have the opposite effect, directing cell cycle exit in a number of cell types in vertebrate and in invertebrate embryos.
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Cooperating morphogens control hoxd gene expression in the developing vertebrate limb.
A mechanism was recently proposed which controls the expression of Hoxa genes in the developing vertebrate limb. This is a three-dimensional diffusion model of a morphogen Ma secreted at the apical ectodermal ridge. The morphogen Ma is at the same time degraded by first order chemical kinetics. The emerging diffusion gradient, supplemented with a natural sequence of thresholds, can explain the spatial and temporal collinearities of the Hoxa gene expression domains. In the present model it is assumed that a second diffusing morphogen Mz is produced at the zone of polarizing activity. A concentration superposition of morphogens Ma and Mz can then explain the observed pattern of expression of Hoxd-10, 11, 12, and 13 during normal limb development (spatial and temporal collinearity). The associated thresholds for gene expression increase sequentially from Hoxd-10 to Hoxd-13 (threshold collinearity). The observed deformations or deletions of these expression domains in manipulated limbs are also explained by the model. Additional model predictions are proposed to test the validity of the model. In patterning two mechanisms are mainly considered as responsible for signalling: (i) a gradient of a long-range morphogen created by passive diffusion; and (ii) a short-range inducer initiating a cascade of consecutive signals. A time-test is proposed which distinguishes the modes of specific gene expressions for these distinct signalling mechanisms.
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Genetics of photoreceptor development and function in zebrafish.
The vertebrate photoreceptor is a cell of unique morphology and function. It is an exquisite light detector, both sensitive and adaptable. Several unusual morphological features facilitate photoreceptor function. Signal detection is accomplished by a specialized apical structure, the outer segment. There, the capture of light produces fluctuations in cell membrane potential, which are then transmitted to the downstream circuitry of the retina via a rare type of synaptic junction, the ribbon synapse. The development, maintenance and function of the vertebrate photoreceptor cell have been studied mainly in four model organisms, ranging from an amphibian to man. A teleost fish, the zebrafish, is an important recent addition to this group. Genetic screens in zebrafish have identified an impressive collection of photoreceptor cell mutants, including the absence or malformation of specific morphological features as well as functional abnormalities. These mutant strains are currently studied using both molecular and embryological tools and provide important insights into photoreceptor biology.
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Cloning and characterization of a cDNA encoding the collagen-binding stress protein hsp47 in zebrafish.
Hsp47 is a major stress-inducible protein that is localized to the endoplasmic reticulum of avian and mammalian cells and is thought to act as a molecular chaperone specific for the processing of procollagen. Although hsp47 is coordinately expressed together with several collagen types, and vertebrate embryos are known to express collagen genes in complex spatial and temporal patterns, limited information is available regarding the function or regulation of hsp47 during early embryonic development. We have initiated an examination of hsp47 in the zebrafish, Danio rerio, which offers a number of features that make it attractive as a model developmental system with which to examine the expression and function of hsp47. A polymerase chain reaction (PCR)-based cloning strategy was used to isolate a hsp47 cDNA from an embryonic zebrafish cDNA library. The deduced translation product of the cDNA is a 404-amino-acid polypeptide that is 72% identical to chicken, 64% identical to mouse and rat, and 69% identical to human hsp47. The protein contains a typical hydrophobic signal sequence, an RDEL endoplasmic reticulum retention signal, and a serine protease inhibitor signature sequence, all of which are characteristic of hsp47 in higher vertebrates. Thus, it is likely that hsp47 in zebrafish is also localized to the endoplasmic reticulum and may play a similar role to its counterpart in higher vertebrates. Northern blot analysis revealed that the hsp47 gene is expressed at relatively low levels in embryos during normal development but is strongly induced following exposure to heat shock at the gastrula, midsomitogenesis, 2-day, and 3-day larval stages. The level of induction was much higher than has previously been reported in chicken and mouse cells.
Amino Acid Sequence↗
Developmental toxicity of the dithiocarbamate pesticide sodium metam in zebrafish.
Sodium metam (NaM), a dithiocarbamate, is a general agricultural biocide applied prior to planting for the elimination of nematodes, soil pathogens, and weeds. There is a remarkable paucity of information about the mechanism of action and the risk that dithiocarbamates may pose to developing vertebrates. We have characterized NaM toxicity during early life stage exposure in zebrafish. Zebrafish embryos are most sensitive to NaM exposure during gastrulation and early segmentation (4-14 hours post fertilization, hpf). For mortality, the dose response curve is steep with an LC(50) estimate of 1.95 microM (248 ppb) at 48 hpf. The most notable malformation among surviving embryos was a severely twisted notochord, which became evident by 24 hpf. Surprisingly, this notochord defect was not immediately lethal and the animals continued to grow despite delays in hatching, apparent paralysis, and an inability to feed. We have characterized the notochord malformation using histological and in situ hybridization techniques. collagen 2a1 mRNA expression is normally localized to the notochord sheath cells at 24 hpf, whereas in NaM-exposed embryos it is misexpressed in the notochord cells. Histological staining and myoD expression indicate that the myotomes of the NaM-exposed embryos are less defined, compacted and block-shaped compared to controls. The degradation product of NaM, methyl isothiocyanate (MITC), causes similar malformations at similar concentrations as NaM, suggesting that MITC or another common product may be the active toxicant. Our results indicate that developing zebrafish are sensitive to NaM and MITC and we believe that this model is ideal to elucidate the molecular mechanism(s) and etiology of NaM toxicity in vertebrates.
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Asymmetry of intronic pre-miRNA structures in functional RISC assembly.
The two oligonucleotide strands of a siRNA duplex are functionally asymmetric in assembling the RNAi effector, RNA-induced gene silencing complex (RISC). Based on this asymmetric RISC assembly model in vitro, formation of a microRNA (miRNA) and complementary miRNA (miRNA*) duplex was proposed to be an essential step for the assembly of miRNA-associated RISC (miRISC). We observed here that a strong structural bias exists in the selection of a mature miRNA strand for RISC assembly in zebrafish using an intronic miRNA-like vector to target EGFP mRNA for regulation. The position of the stemloop in a precursor miRNA (pre-miRNA) was involved in the determination of miRNA-miRNA* asymmetry of the pre-miRNA stemarm, leading to different miRNA maturation during miRISC assembly. These findings suggest that the miRISC assembly is likely different from the RISC assembly model of siRNA in zebrafish, providing the first in vivo evidence for asymmetric miRISC assembly.
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Cancer genetics and drug discovery in the zebrafish.
Fish have a long history of use in cancer toxicology studies, because they develop neoplasms that are histologically similar to human cancers. Because of considerable progress in zebrafish genetics and genomics over the past few years, the zebrafish system has provided many useful tools for studying basic biological processes. These tools include forward genetic screens, transgenic models, specific gene disruptions and small-molecule screens. By combining carcinogenesis assays, genetic analyses and small-molecule screening techniques, the zebrafish is emerging as a powerful system for identifying novel cancer genes and for cancer drug discovery.
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Homologous recombination and DNA-end joining reactions in zygotes and early embryos of zebrafish (Danio rerio) and Drosophila melanogaster.
A linear DNA with partial sequence redundancy can be recircularized in cells by either nonhomologous end joining (NEJ) or by homologous recombination (HR). We have studied the relative contributions of these processes in zygotes or early embryos of species that serve as model organisms for developmental genetics. Thus, we have microinjected a linearized plasmid substrate into zygotes of zebrafish (Danio rerio) or into the posterior end of Drosophila melanogaster early embryos before pole cell formation. Similar to the situation observed previously in Xenopus zygotes/early embryos, we detected a large preponderance of DNA-end joining over homologous recombination. A comparison of end-joined junctions revealed that from the three species tested, zebrafish introduced the least number of sequence distortions upon DNA-end joining, while Drosophila produced the largest deletions (average 14 bp) with occasional nucleotide patch insertions, reminiscent of the N nucleotides at V(D)J junctions in mammalian immune receptor genes. Double-strand gap repair by homologous sequences ('homologous recombination') involving a bimolecular reaction was readily detectable in both zebrafish and Drosophila. This involved specifically designed recombination substrates consisting of a mutagenized linear plasmid and DNA fragments carrying the wild-type sequence. Our results show that the basic machinery for homologous recombination is present at early developmental stages of these two genetic model organisms. However, it seems that for any experimental exploitation, such as targeted gene disruption, one would have to inhibit or bypass the overwhelming DNA-end joining activity.
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Myogenic regulatory factors Myf5 and Myod function distinctly during craniofacial myogenesis of zebrafish.
The functions of Myf5 and Myod are well known in trunk myogenesis. However, the roles that Myf5 and Myod play during craniofacial myogenesis are far from well known. We observed that zebrafish myf5 was detected in the primordia of the obliques, lateral rectus, sternohyoideus, and pharyngeal mesoderm cores. In contrast, myod transcripts were expressed in all head muscle precursors at later stages. Knockdown of myf5 revealed that Myf5 was required for the development of the obliques, lateral rectus, sternohyoideus, and all pharyngeal muscles, whereas knockdown of myod proved that Myod was required for the development of superior rectus, medial rectus, inferior rectus, lateral rectus, and the ventral pharyngeal muscles. myod mRNA did not rescue the loss of the cranial muscle caused by injecting myf5-morpholino, or vice versa, suggesting that the functions of Myf5 and Myod were not redundant in head paraxial mesoderm, a finding different from their functions in trunk myogenesis. Myf5, but not Myod, was required for the forward migration of myf5-positive oblique precursors. All evidences reveal that Myf5 and Myod function independently during cranial myogenesis. On the basis of the expression patterns of myf5 and myod, we propose a model to present how Myf5 and Myod are involved in head myogenesis of zebrafish.
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Characterisation of Fmrp in zebrafish: evolutionary dynamics of the fmr1 gene.
Fragile X syndrome is the most common inherited form of mental retardation. It is caused by the lack of the Fragile X Mental Retardation Protein (FMRP), which is encoded by the FMR1 gene. Although Fmr1 knockout mice display some characteristics also found in fragile X patients, it is a complex animal model to study brain abnormalities, especially during early embryonic development. Interestingly, the ortholog of the FMR1 gene has been identified not only in mouse, but also in zebrafish (Danio rerio). In this study, an amino acid sequence comparison of FMRP orthologs was performed to determine the similar regions of FMRP between several species, including human, mouse, frog, fruitfly and zebrafish. Further characterisation of Fmrp has been performed in both adults and embryos of zebrafish using immunohistochemistry and western blotting with specific antibodies raised against zebrafish Fmrp. We have demonstrated a strong Fmrp expression in neurons of the brain and only a very weak expression in the testis. In brain tissue, a different distribution of the isoforms of Fmrp, compared to human and mouse brain tissue, was shown using western blot analysis. Due to the high similarity between zebrafish Fmrp and human FMRP and their similar expression pattern, the zebrafish has great potential as a complementary animal model to study the pathogenesis of the fragile X syndrome, especially during embryonic development.
Amino Acid Sequence↗
Postembryonic neural proliferation in the zebrafish forebrain and its relationship to prosomeric domains.
Large gaps of knowledge exist regarding postembryonic brain morphogenesis of the zebrafish Danio rerio (Cyprinidae, Teleostei). The zebrafish represents together with the frog (Xenopus), chick and mouse--one of four major models for the genetic study of early brain development. Here, we used normal silver-stained Bodian material and immunohistochemical material stained with a monoclonal antibody against the proliferating cell nuclear antigen (PCNA, cyclin) to study the morphogenetic appearance and location of proliferation zones of the zebrafish brain between day 1 and day 10, focussing on the forebrain at day 5 postfertilization. Our results directly demonstrate that the dorsal telencephalic proliferation zone (i.e. the pallium) extends--consistent with the process of eversion--some distance laterally on top of the telencephalon. The subpallial telencephalic proliferation consists of dorsal and ventral zones. The preoptic region also includes dorsal and ventral proliferation zones. In the diencephalon proper, separate proliferation zones are present in the habenula, and in the periventricular cell masses of the dorsal thalamus, the ventral thalamus, and the pretectum. More ventrocaudally, the latter three massive proliferation zones appear to be replaced each by thinner, but distinct proliferation zones. Two of them represent ventrocaudal continuations of the dorsal and ventral thalamus and lie in the region referred to as the posterior tubercular area in adult teleostean neuroanatomy. The third lies in the region of the nucleus of the medial longitudinal fascicle. In addition, several hypothalamic proliferation zones are present. The data for the diencephalon are largely in agreement with the neuromeric model of brain organization of Puelles and Rubenstein (1993), which is mostly based on amniote data. Generally, the understanding of the prosomeric origin of teleostean prosencephalic cell masses may be regarded as pivotal for their comparative interpretation.
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