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At least 253 records · Page 14Linked to original sources
PubMed2005

Effects of selected xenoestrogens on liver peroxisomes, vitellogenin levels and spermatogenic cell proliferation in male zebrafish.

Environmental estrogenic compounds or xenoestrogens can mimic natural estrogens and cause a variety of adverse effects on aquatic wildlife. The purpose of the present work was to investigate if xenoestrogens are able to cause proliferation of liver peroxisomes using zebrafish (Danio rerio) as a model. Adult male zebrafish were exposed for 15 days to 17beta-estradiol (E2) and the xenoestrogens dibutylphthalate (DBP), methoxychlor (MXC), 4-tert-octylphenol (OP) and 17alpha-ethynylestradiol (EE2). All five tested compounds caused significant proliferation of liver peroxisomes (p < 0.05) as indicated by increased peroxisomal surface and numerical densities and elevated activities of the peroxisomal beta-oxidation enzyme acyl-CoA oxidase (AOX). In the case of DBP, MXC and E2, positive significant correlations between peroxisomal density parameters and AOX were found. The treatments did not produce gross alterations in testis histology, but spermatogenic cell proliferation was disturbed in E2 and EE2-treated groups and vitellogenin levels increased significantly in fish exposed to MXC, OP, EE2 and E2 with respect to controls. Furthermore, a significant correlation between vitellogenin levels and AOX activity was found for MXC, OP and EE2 treatments, suggesting that for the latter xenoestrogens early estrogenic effects are associated with liver peroxisome proliferation. No such association occurred with typical peroxisome proliferators such as DBP.

Acyl-CoA Oxidase↗
PubMedDate not supplied

Ethanol- and acetaldehyde-mediated developmental toxicity in zebrafish.

Ethanol is a well-established developmental toxicant; however, the mechanism(s) of this toxicity remains unclear. Zebrafish are becoming an important model system for the evaluation of chemical and drug toxicity. In this study, zebrafish embryos were utilized to compare the developmental toxicity resulting from either ethanol or acetaldehyde exposure. Embryos were exposed to waterborne ethanol concentrations for various lengths of time but encompassed the earliest stages of embryogenesis. The waterborne ethanol concentration that causes 50% mortality (LC(50)) following a 45-h ethanol exposure was approximately 340 mM (1.98% v/v). A number of reproducible endpoints resulted from ethanol exposure and included pericardial edema, yolk sac edema, axial malformations, otolith defects, delayed development, and axial blistering. When the exposure period was reduced, similar signs of toxicity were produced at nearly identical ethanol concentrations. To estimate the embryonic dose following a given waterborne ethanol concentration, a kinetic alcohol dehydrogenase (ADH) assay was adapted. The average embryonic ethanol dose was calculated to be a fraction of the waterborne concentration. Embryos exposed to waterborne acetaldehyde resulted in similar, but not identical, endpoints as those induced by ethanol. Embryos were however, almost three orders of magnitude more sensitive to acetaldehyde than to ethanol. Ethanol and acetaldehyde both negatively impact embryonic development; however, ethanol is more teratogenic based on teratogenic indices (TIs). These results demonstrate that the zebrafish model will provide an opportunity to further evaluate the mechanism of action of ethanol on vertebrate development.

Abnormalities, Multiple↗
PubMed2004

Prostaglandin E synthases in zebrafish.

OBJECTIVE: Prostaglandin E synthases (PGESs) are being explored as antiinflammatory drug targets as alternatives to cyclooxygenase (COX)-2. Located downstream of the cyclooxygenases, PGESs catalyze PGE(2) formation, and deletion of microsomal (m)-PGES-1 abrogates inflammation. We sought to characterize the developmental expression of COX and PGES in zebrafish. METHODS AND RESULTS: We cloned zebrafish cytosolic (c) and m-PGES orthologs and mapped them to syntenic regions of chromosomes 23 and 5. cPGES was widely expressed during development and was coordinately regulated with zCOX-1 in the inner ear, the pronephros, and intestine. COX-2 and mPGES-1 exhibited restricted expression, dominantly in the vasculature of the aortic arch. However, the enzymes were anatomically segregated within the vessel wall. Experiments with antisense morpholinos and with nonsteroidal antiinflammatory drugs suggest that these genes may not be critical for development. CONCLUSIONS: mPGES-1 is developmentally coregulated with COX-2 in vasculature. Given the high fecundidity and translucency of the zebrafish, this model may afford a high throughput system for characterization of novel PGES inhibitors. Microsomal prostaglandin E synthase (mPGES)-1, located downstream of COX-2, may represent a novel antiinflammatory drug target. Zebrafish cytosolic (c) PGES-1 and COX-1 were coordinately expressed; mPGES-1 and COX-2 were expressed particularly in the vasculature. Zebrafish may afford a high throughput system for detection of novel PGES inhibitors.

Animals↗
PubMedDate not supplied

Effects of dizocilpine (MK-801) on circling behavior, swimming activity, and place preference in zebrafish (Danio rerio).

Glutamate transmission plays an important role in many behavioral systems, including motor activity, learning, and memory. The noncompetitive NMDA receptor antagonist (+)MK-801 has been shown to increase motor activity and impair learning and memory in a variety of tasks in rats, mice, and other species. In an attempt to characterize the effects of MK-801 on motor activity and cognitive performance in an emerging neurobehavioral model, the zebrafish (Danio rerio), we examined the effects of MK-801 on circling behavior, swimming activity, and latency to enter, as well as preference for, an enriched chamber (EC). In Experiment 1, the effects of a 37-min acute exposure to (+)MK-801 (0, 2.0, and 20.0 microM) on circling behavior were measured in a round observation chamber. (+)MK-801 was observed to increase circling behavior in a dose-dependent manner. In the second experiment, fish were treated with 0, 2, 20, or 200 microM (+)MK-801 for 1 h, and swimming activity was measured in a rectangular observation chamber for 60 min following dosing. The lowest dose of (+)MK-801 decreased swimming activity. In the third experiment, fish were treated with either 0 or 20 microM (+)MK-801 for 1 h each day over four consecutive days. The fish were tested in a modified T-maze to assess both latency to enter, and preference for, an EC 24, 27, and 48 h after the last treatment. The results showed that untreated fish exhibited a preference for the EC at the 27- and 48-h trials, but (+)MK-801-treated fish did not exhibit a preference for the EC at any trial. No significant reduction in latency to enter the chamber was found for either treated or control fish. Together, the results of these experiments suggest that NMDA receptor antagonism (1) increases circling behavior, (2) alters swimming activity, and (3) impairs place preference. These findings lend further support for the usefulness of the zebrafish for assessing the acute and chronic exposure effects of water-soluble compounds on motor and cognitive functions.

Animals↗
PubMed2004

Molecular cloning, characterization, and expression in brain and gonad of Dmrt5 of zebrafish.

The DM domain gene family has at least eight members with conserved DNA-binding DM domain, which encodes putative transcription factors related to the sexual regulator Dsx of Drosophila and Mab-3 of Caenorhabditis elegans. Although some of the DM genes are involved in sexual development, the function of most of these genes remains unclear. There is also few structural and functional analysis concerning DM domain genes of the model fish, zebrafish. We report here molecular cloning, sequence, and expression of zebrafish Dmrt5, which consists of two exons, and encodes a 440-amino acid protein with conserved DMA and DMB domains in addition to DM domain. Phylogenetic analysis shows that zebrafish Dmrt5 fits within the Dmrt5 clade of fish and mammals. Zebrafish Dmrt5 was expressed in early gastrula period, subsequently increased to a high level in late stage of gastrula period (bud stage) and lower until the hatch period. In situ hybridization analysis showed its expression in developing central nervous system of embryos, especially in mid-brain and mid-hind brain boundary. In adult, its expression was restricted in brain and developing germ cells, especially in spermatogonia, spermatocytes, spermatids, and sperm cells, and in developing oocytes, including early perinucleolus stage oocyte, late yolk vesicle stage oocyte, and oil drop stage oocyte. These data suggest that zebrafish Dmrt5 have potentially important roles in gonadal development and may have contributed to the functional endocrine axis.

Amino Acid Sequence↗
PubMed2001

Demonstration of the extrinsic coagulation pathway in teleostei: identification of zebrafish coagulation factor VII.

It is not known whether the mammalian mechanism of coagulation initiation is conserved in fish. Identification of factor VII is critical in providing evidence for such a mechanism. A cDNA was cloned from a zebrafish (teleost) library that predicted a protein with sequence similarity to human factor VII. Factor VII was shown to be present in zebrafish blood and liver by Western blot analysis and immunohistochemistry. Immunodepletion of factor VII from zebrafish plasma selectively inhibited thromboplastin-triggered thrombin generation. Heterologous expression of zebrafish factor VII demonstrated a secreted protein (50 kDa) that reconstituted thromboplastin-triggered thrombin generation in immunodepleted zebrafish plasma. These results suggest conservation of the extrinsic coagulation pathway between zebrafish and humans and add credence to the zebrafish as a model for mammalian hemostasis. The structure of zebrafish factor VIIa predicted by homology modeling was consistent with the overall three-dimensional structure of human factor VIIa. However, amino acid disparities were found in the epidermal growth factor-2/serine protease regions that are present in the human tissue factor-factor VIIa contact surface, suggesting a structural basis for the species specificity of this interaction. In addition, zebrafish factor VII demonstrates that the Gla-EGF-EGF-SP domain structure, which is common to coagulation factors VII, IX, X, and protein C, was present before the radiation of the teleosts from the tetrapods. Identification of zebrafish factor VII significantly narrows the evolutionary window for development of the vertebrate coagulation cascade and provides insight into the structural basis for species specificity in the tissue factor-factor VIIa interaction.

Amino Acid Sequence↗
PubMed2005

Characterization of MtsR, a new metal regulator in group A streptococcus, involved in iron acquisition and virulence.

Group A streptococcus (GAS) is a common pathogen of the human skin and mucosal surfaces capable of producing a variety of diseases. In this study, we investigated regulation of iron uptake in GAS and the role of a putative transcriptional regulator named MtsR (for Mts repressor) with homology to the DtxR family of metal-dependent regulatory proteins. An mtsR mutant was constructed in NZ131 (M49 serotype) and analyzed. Western blot and RNA analysis showed that mtsR inactivation results in constitutive transcription of the sia (streptococcal iron acquisition) operon, which was negatively regulated by iron in the parent strain. A recombinant MtsR with C-terminal His(6) tag fusion (rMtsR) was cloned and purified. Electrophoretic mobility gel shift assays demonstrated that rMtsR specifically binds to the sia promoter region in an iron- and manganese-dependent manner. Together, these observations indicate that MtsR directly represses the sia operon during cell growth under conditions of high metal levels. Consistent with deregulation of iron uptake, the mtsR mutant is hypersensitive to streptonigrin and hydrogen peroxide, and (55)Fe uptake assays demonstrate that it accumulates 80% +/- 22.5% more iron than the wild-type strain during growth in complete medium. Studies with a zebrafish infection model revealed that the mtsR mutant is attenuated for virulence in both the intramuscular and the intraperitoneal routes. In conclusion, MtsR, a new regulatory protein in GAS, controls iron homeostasis and has a role in disease production.

Amino Acid Sequence↗
PubMed2000

Optokinetic behavior is reversed in achiasmatic mutant zebrafish larvae.

The vertebrate optokinetic nystagmus (OKN) is a compensatory oculomotor behavior that is evoked by movement of the visual environment. It functions to stabilize visual images on the retina. The OKN can be experimentally evoked by rotating a drum fitted with stripes around the animal and has been studied extensively in many vertebrate species, including teleosts. This simple behavior has earlier been used to screen for mutations affecting visual system development in the vertebrate model organism zebrafish. In such a screen, we have found a significant number of homozygous belladonna (bel) mutant larvae to be defective in the correct execution of the OKN [1]. We now show that about 40% of homozygous bel larvae display a curious reversal of the OKN upon visual stimulation. Monocular stimulation leads to primary activation of ipsilateral eye movements in larvae that behave like the wild type. In contrast, affected larvae display contralateral activation of eye movements upon monocular stimulation. Anatomical analysis of retinal ganglion cell axon projections reveal a morphological basis for the observed behavioral defect. All animals with OKN reversal are achiasmatic. Further behavioral examination of affected larvae show that OKN-reversed animals execute this behavior in a stimulus-velocity-independent manner. Our data support a parsimonious model of optokinetic reversal by the opening of a controlling feedback loop at the level of the optic chiasm that is solely responsible for the observed behavioral abnormality in mutant belladonna larvae.

Animals↗
PubMed2006

Frequency-dependent modulation of glycine receptor activation recorded from the zebrafish larvae hindbrain.

In vertebrates, most glycinergic inhibitory neurons discharge phasically at a relatively low frequency. Such a pattern of glycine liberation from presynaptic terminals may affect the kinetics of post-synaptic glycine receptors. To examine this influence, we have analyzed the behavior of glycine receptors in response to repetitive stimulation at frequencies at which consecutive outside-out currents did not superimpose (0.5-4 Hz). Neurotransmitter release was mimicked on outside-out patches from zebrafish hindbrain Mauthner cells using fast flow application techniques. The amplitude of outside-out currents evoked by short (1 ms) repetitive applications of a saturating concentration (3 mM) of glycine remained unchanged for application frequencies 1 Hz. Glycine-evoked current simulations using a simple Markov model describing zebrafish glycine receptor kinetic behavior, indicates that this down-regulation of glycine receptor efficacy is due to a progressive accumulation of the receptors in a long lasting desensitization state. Our simulations suggest that this down-regulation can occur even when spontaneous inhibitory currents were generated randomly at a frequency>1 Hz.

Animals↗
PubMed2004

Suppression of apoptosis by bcl-2 overexpression in lymphoid cells of transgenic zebrafish.

The zebrafish is an attractive vertebrate model for genetic studies of development, apoptosis, and cancer. Here we describe a transgenic zebrafish line in which T- and B-lymphoid cells express a fusion transgene that encodes the zebrafish bcl-2 protein fused to the enhanced green fluorescence protein (EGFP). Targeting EGFP-bcl-2 to the developing thymocytes of transgenic fish resulted in a 2.5-fold increase in thymocyte numbers and a 1.8-fold increase in GFP-labeled B cells in the kidney marrow. Fluorescent microscopic analysis of living rag2-EGFP-bcl-2 transgenic fish showed that their thymocytes were resistant to irradiation- and dexamethasone-induced apoptosis, when compared with control rag2-GFP transgenic zebrafish. To test the ability of bcl-2 to block irradiation-induced apoptosis in malignant cells, we compared the responsiveness of Myc-induced leukemias with and without EGFP-bcl-2 expression in living transgenic zebrafish. T-cell leukemias induced by the rag2-EGFP-Myc transgene were ablated by irradiation, whereas leukemias in double transgenic fish expressing both Myc and EGFP-bcl-2 were resistant to irradiation-induced apoptotic cell death. The forward genetic capacity of the zebrafish model system and the ability to monitor GFP-positive thymocytes in vivo make this an ideal transgenic line for modifier screens designed to identify genetic mutations or small molecules that modify bcl-2-mediated antiapoptotic pathways.

Amino Acid Sequence↗
PubMed2004

Enhancer trapping in zebrafish using the Sleeping Beauty transposon.

BACKGROUND: Among functional elements of a metazoan gene, enhancers are particularly difficult to find and annotate. Pioneering experiments in Drosophila have demonstrated the value of enhancer "trapping" using an invertebrate to address this functional genomics problem. RESULTS: We modulated a Sleeping Beauty transposon-based transgenesis cassette to establish an enhancer trapping technique for use in a vertebrate model system, zebrafish Danio rerio. We established 9 lines of zebrafish with distinct tissue- or organ-specific GFP expression patterns from 90 founders that produced GFP-expressing progeny. We have molecularly characterized these lines and show that in each line, a specific GFP expression pattern is due to a single transposition event. Many of the insertions are into introns of zebrafish genes predicted in the current genome assembly. We have identified both previously characterized as well as novel expression patterns from this screen. For example, the ET7 line harbors a transposon insertion near the mkp3 locus and expresses GFP in the midbrain-hindbrain boundary, forebrain and the ventricle, matching a subset of the known FGF8-dependent mkp3 expression domain. The ET2 line, in contrast, expresses GFP specifically in caudal primary motoneurons due to an insertion into the poly(ADP-ribose) glycohydrolase (PARG) locus. This surprising expression pattern was confirmed using in situ hybridization techniques for the endogenous PARG mRNA, indicating the enhancer trap has replicated this unexpected and highly localized PARG expression with good fidelity. Finally, we show that it is possible to excise a Sleeping Beauty transposon from a genomic location in the zebrafish germline. CONCLUSIONS: This genomics tool offers the opportunity for large-scale biological approaches combining both expression and genomic-level sequence analysis using as a template an entire vertebrate genome.

Animals↗
PubMed2004

Duplicate zebrafish runx2 orthologues are expressed in developing skeletal elements.

The differentiation of cells in the vertebrate skeleton is controlled by a precise genetic program. One crucial regulatory gene in the pathway encodes the transcription factor Runx2, which in mouse is required for differentiation of all osteoblasts and the proper development of a subset of hypertrophic chondrocytes. To explore the differentiation of skeletogenic cells in the model organism zebrafish (Danio rerio), we have identified two orthologues of the mammalian gene, runx2a and runx2b. Both genes share sequence homology and gene structure with the mammalian genes, and map to regions of the zebrafish genome displaying conserved synteny with the region where the human gene is localized. While both genes are expressed in developing skeletal elements, they show evidence of partial divergence in expression pattern, possibly explaining why both orthologues have been retained through teleost evolution.

Amino Acid Sequence↗
PubMed2003

Targeted gene knockdown in zebrafish using negatively charged peptide nucleic acid mimics.

Negatively charged homo-oligomers of alternating trans-4-hydroxy-L-proline/phosphonate polyamides with DNA bases (HypNA-pPNA) display excellent hybridization properties toward DNA and RNA, while preserving the mismatch discrimination, nuclease resistance, and protease resistance of peptide nucleic acids (PNAs). Similar properties are associated with morpholino phosphorodiamidate (MO) DNA mimics, which have been used in the model vertebrate zebrafish (Danio rerio) for genome-wide, sequence-based, reverse genetic screens during embryonic development. We evaluated mixed sequence HypNA-pPNAs as an alternative to MOs, and found that even a single central DNA mismatch lowered the HypNA-pPNA melting temperature by 16 degrees C. We then observed that the melting temperatures of HypNA-pPNA 18-mers hybridized to RNA 25-mers were comparable to the melting temperatures of MO 25-mers, and that two HypNA-pPNA mismatches lowered the melting temperature with RNA by 18 degrees C. In zebrafish embryos we observed that HypNA-pPNA 18-mers displayed comparable potency to MO 25-mers as knockdown agents against chordin, notail, and uroD, with greater mismatch stringency. Finally we observed that a specific HypNA-pPNA 18-mer elicited the dharma (bozozok)(-/-) phenotype in zebrafish embryos, which MO 25-mers do not. HypNA-pPNAs designed to inhibit translation of specific zebrafish RNA targets thus demonstrated stringent hybridization properties, relative to DNA and MO oligomers, and present a valuable alternative for reverse genetic studies, enabling the targeting of previously inaccessible genes.

Animals↗
PubMed2002

Search for enhancers: teleost models in comparative genomic and transgenic analysis of cis regulatory elements.

Homology searches between DNA sequences of evolutionary distant species (phylogenetic footprinting) offer a fast detection method for regulatory sequences. Because of the small size of their genomes, tetraodontid species such as the Japanese pufferfish and green spotted pufferfish have become attractive models for comparative genomics. A disadvantage of the tetraodontid species is, however, that they cannot be bred and manipulated routinely under laboratory conditions, so these species are less attractive for developmental and genetic analysis. In contrast, an increasing arsenal of transgene techniques with the developmental model species zebrafish and medaka are being used for functional analysis of cis regulatory sequences. The main disadvantage is the much larger genome. While comparison between many loci proved the suitability of phylogenetic footprinting using fish and mammalian sequences, fast rate of change in enhancer structure and gene duplication within teleosts may obscure detection of homologies. Here we discuss the contribution and potentials provided by different teleost models for the detection and functional analysis of conserved cis-regulatory elements.

Animals↗
PubMed2026

First characterization of Staphylococcus felis in diabetic foot osteomyelitis: from intracellular persistence to phage treatment.

Staphylococcus felis is a coagulase-negative Staphylococcus (CoNS) primarily associated with the feline microbiota and only rarely reported in human disease. Here, we report its implication in diabetic foot osteomyelitis, and provide the first comprehensive characterization of its pathogenic potential. Two isolates (NSF001 and NSF002), recovered 5 months apart from bone biopsies of the same patient, were analyzed for growth kinetics, biofilm formation, and intracellular persistence in macrophages and osteoblasts. Both isolates proliferated efficiently, produced robust biofilm, and persisted within host cells, most markedly in osteoblasts. In a zebrafish embryo infection model, both isolates caused significant mortality, confirming their pathogenic potential in vivo. Whole-genome sequencing revealed conserved virulence determinants, a narrow resistome, and strain-specific genomic variations affecting genes involved in virulence regulation, phage defense, and iron acquisition. The lytic phage SAVM02, previously characterized for activity against other Staphylococcus species, effectively inhibited S. felis growth in vitro and conferred protection in vivo against lethal infection. Notably, the two sequential isolates differed in their in vivo virulence and phage susceptibility, paralleling these within-host microevolutionary changes and illustrating bacterial adaptation during chronic infection. Altogether, this study establishes S. felis as a CoNS capable of intracellular persistence, biofilm formation, and in vivo virulence in chronic human infection. Our findings also highlight the therapeutic potential of lytic phages against virulent CoNS species and support further investigation of phage therapy for chronic staphylococcal infections.IMPORTANCECoagulase-negative staphylococci (CoNS) are increasingly recognized as genuine agents of chronic infection, yet the pathogenic capacity of most individual species remains undefined. Staphylococcus felis, a commensal of cats only exceptionally reported in humans, had never been implicated in a chronic human infection. Here, we describe two sequential S. felis isolates recovered from bone biopsies of a patient with diabetic foot osteomyelitis and show that this species combines biofilm formation, intracellular persistence in macrophages and osteoblasts, and lethality in a zebrafish embryo model. Whole-genome comparison of the two isolates uncovered microevolutionary changes, most notably in iron-acquisition and genome-defense loci, that paralleled differences in virulence and phage susceptibility. These findings extend the list of CoNS capable of causing invasive human disease and provide a rationale for lytic phage therapy against emerging, difficult-to-treat staphylococcal pathogens.

Staphylococcus felis↗
PubMedDate not supplied

A morphological classification of ganglion cells in the zebrafish retina.

We examined the distribution and morphological types of ganglion cells in the retina of the zebrafish, a model vertebrate genetic organism. Using cresyl violet and methylene blue staining, a prominent central area was observed in the ventral temporal retina. The density of ganglion cell layer neurons averaged from approximately 12,000/mm2 in the dorsal-nasal retina to a peak of approximately 37,000/mm2 in the ventral-temporal retina. Individual zebrafish ganglion cells were labeled by backfilling with DiI through the optic nerve followed by reconstruction using confocal microscopy. The dendritic stratification and branching pattern of each labeled ganglion cell was examined in relation to the borders of the inner plexiform layer (IPL). We identified 11 different morphological types of ganglion cell. The most commonly labeled ganglion cells were two types termed Type III or IV, which displayed highly stratified dendritic arborizations in their respective ON-, OFF-sublaminae of the IPL. Their dendritic branching patterns were highly asymmetric with many thorn-like varicosities that profusely filled the area of arborization. In contrast, Type V cells formed a small simply branching dendritic field in the innermost portion of the ON-sublamina of the IPL. Two large ganglion cell types (Types I and II) with wide monostratified dendritic fields were found in both the ON- and OFF-sublamina of the IPL. Three different types of multistratified/bistratified ganglion cells were found (Types, IX, X, and XI.) whose dendrites occupied different regions of the IPL. The multistratified dendrites of IX cells occupied the whole width of the IPL, while the dendrites of Type XI cells formed vertical claw-like endings in only the ON-sublamina of the IPL. We conclude that zebrafish ganglion cells display a rich variety of types and branching patterns. This study establishes a series of baseline measurements of zebrafish ganglion cells to facilitate examination of genes playing a role in the specification and stratification of ganglion cell types.

Animals↗
PubMed2005

Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo.

Chemically induced birth defects are an important public health and human problem. Here we use Xenopus and zebrafish as models to investigate the mechanism of action of a well-known teratogen, valproic acid (VPA). VPA is a drug used in treatment of epilepsy and bipolar disorder but causes spina bifida if taken during pregnancy. VPA has several biochemical activities, including inhibition of histone deacetylases (HDACs). To investigate the mechanism of action of VPA, we compared its effects in Xenopus and zebrafish embryos with those of known HDAC inhibitors and noninhibitory VPA analogs. We found that VPA and other HDAC inhibitors cause very similar and characteristic developmental defects whereas VPA analogs with poor inhibitory activity in vivo have little teratogenic effect. Unbiased microarray analysis revealed that the effects of VPA and trichostatin A (TSA), a structurally unrelated HDAC inhibitor, are strikingly concordant. The concordance is apparent both by en masse correlation of fold-changes and by detailed similarity of dose-response profiles of individual genes. Together, the results demonstrate that the teratogenic effects of VPA are very likely mediated specifically by inhibition of HDACs.

Abnormalities, Drug-Induced↗
PubMed2002

The role of the Eph-ephrin signalling system in the regulation of developmental patterning.

The Eph and ephrin system, consisting of fourteen Eph receptor tyrosine kinase proteins and nine ephrin membrane proteins in vertebrates, has been implicated in the regulation of many critical events during development. Binding of cell surface Eph and ephrin proteins results in bi-directional signals, which regulate the cytoskeletal, adhesive and motile properties of the interacting cells. Through these signals Eph and ephrin proteins are involved in early embryonic cell movements, which establish the germ layers, cell movements involved in formation of tissue boundaries and the pathfinding of axons. This review focuses on two vertebrate models, the zebrafish and mouse, in which experimental perturbation of Eph and/or ephrin expression in vivo have provided important insights into the role and functioning of the Eph/ephrin system.

Amino Acid Sequence↗