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PubMed2006

Genomic sequence and spatiotemporal expression comparison of zebrafish mbx1 and its paralog, mbx2.

The expression of midbrain homeobox-1 (mbx1) defines a discrete region in the vertebrate neural plate that will give rise to the mesencephalon, as well as subregions of the diencephalon and retinal field. Here, we report on the identification and cloning of a second Mbx gene in zebrafish, termed mbx2. Genomic sequence comparison suggests that mbx1 and mbx2 are derived from the duplication of a single putative ancestral gene that is conserved in other vertebrates as a single copy gene. Furthermore, phylogenetic analyses indicate that the mbx genes belong to a novel subgroup of paired-like homeobox genes. Finally, quantitative reverse transcriptase-PCR and whole mount in situ hybridization experiments revealed a pattern of partial spatiotemporal expression divergence between the mbx paralogs that correlates with sequence divergence in noncoding regulatory domains. Our data support a subfunctionalization model that may explain the retention of duplicate mbx genes in teleosts.

Amino Acid Sequence↗
PubMed2005

Isolation and characterization of the laure olfactory behavioral mutant in the zebrafish, Danio rerio.

To initiate a genetic analysis of olfactory development and function in the zebrafish, Danio rerio, we developed a behavioral genetic screen for mutations affecting the olfactory sensory system. First, we characterized olfactory responses of wild-type zebrafish to various odors. We found that 3-day-old juvenile zebrafish reacted to the amino acid L-cysteine with an aversive behavioral response. We isolated one mutant, laure (lre), which showed no aversive behavioral response to L-cysteine at 3 days of development, and carried out a preliminary characterization of this mutant's defects. We found that lre mutant fish were also defective in their response to L-serine and L-alanine, but not to taurocholic acid, as young adults. In addition, lre mutant fish had significantly fewer primary olfactory sensory neurons than normal, and the axons of these neurons did not form the characteristic axon termination pattern in the developing olfactory bulb. Nevertheless, the olfactory epithelium of lre mutant fish showed normal or near normal electrophysiological responses to several odorants. Our data suggest that the behavioral defects observed in the lre mutant result from the disruption of the developing olfactory sensory neurons and their axonal connections within the olfactory bulb. The isolation of the lre mutant shows that our behavior-based screen represents a viable approach for carrying out a genetic dissection of olfactory behaviors in this vertebrate model system.

Animals↗
PubMed2004

Guidance of primordial germ cell migration.

Primordial germ cells (PGCs), the progenitors of the gametes, migrate from the position where they are specified towards the region where the gonad develops. To reach their target, the PGCs obtain directional cues from cells positioned along their migration path. One such cue, the chemokine SDF-1, has recently been found to be critical for proper PGC migration in zebrafish and in mice. In Drosophila, too, a molecule that is structurally related to chemokine receptors and is important for PGC migration has been identified. The ability to visualize chemokine-guided migration at a high resolution in vivo in these model organisms provides a unique opportunity to study this process, which is relevant for many events in normal development and disease.

Animals↗
PubMed2000

Pescadillo, a novel cell cycle regulatory protein abnormally expressed in malignant cells.

Using a culture model of glial tumorigenesis, we identified a novel gene that was up-regulated in malignant mouse astrocytes following the loss of p53. The gene represents the murine homologue of pescadillo, an uncharacterized gene that is essential for embryonic development in zebrafish. Pescadillo is a strongly conserved gene containing unique structural motifs such as a BRCA1 C-terminal domain, clusters of acidic amino acids and consensus motifs for post-translational modification by SUMO-1. Pescadillo displayed a distinct spatial and temporal pattern of gene expression during brain development, being detected in neural progenitor cells and postmitotic neurons. Although it is not expressed in differentiated astrocytes in vivo, the pescadillo protein is dramatically elevated in malignant human astrocytomas. Yeast strains harboring temperature-sensitive mutations in the pescadillo gene were arrested in either G(1) or G(2) when grown in nonpermissive conditions, demonstrating that pescadillo is an essential gene in yeast and is required for cell cycle progression. Consistent with the latter finding, DNA synthesis was only observed in mammalian cells expressing the pescadillo protein. These results suggest that pescadillo plays a crucial role in cell proliferation and may be necessary for oncogenic transformation and tumor progression.

Amino Acid Sequence↗
PubMed2001

The zebrafish glypican knypek controls cell polarity during gastrulation movements of convergent extension.

Mutations in the zebrafish knypek locus impair gastrulation movements of convergent extension that narrow embryonic body and elongate it from head to tail. We demonstrate that knypek regulates cellular movements but not cell fate specification. Convergent extension movement defects in knypek are associated with abnormal cell polarity, as mutant cells fail to elongate and align medio-laterally. Positional cloning reveals that knypek encodes a member of the glypican family of heparan sulfate proteoglycans. Double mutant and overexpression analyses show that Knypek potentiates Wnt11 signaling, mediating convergent extension. These studies provide experimental and genetic evidence that glypican Knypek acts during vertebrate gastrulation as a positive modulator of noncanonical Wnt signaling to establish polarized cell behaviors underlying convergent extension movements.

Amino Acid Sequence↗
PubMed2006

Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease.

Primary cilia are implicated in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which results from defects in polycystin-1 (PC1), but the function of PC1 remains poorly understood. Here, we show that PC1 undergoes proteolytic cleavage that results in nuclear translocation of its cytoplasmic tail. The PC1 tail interacts with the transcription factor STAT6 and the coactivator P100, and it stimulates STAT6-dependent gene expression. Under normal conditions, STAT6 localizes to primary cilia of renal epithelial cells. Cessation of apical fluid flow results in nuclear translocation of STAT6. Cyst-lining cells in ADPKD exhibit elevated levels of nuclear STAT6, P100, and the PC1 tail. Exogenous expression of the human PC1 tail results in renal cyst formation in zebrafish embryos. These results identify a novel mechanism of cilia function in the transduction of a mechanical signal to changes of gene expression involving PC1 and show that this pathway is inappropriately activated in ADPKD.

Amino Acid Sequence↗
PubMed1998

Ventral and lateral regions of the zebrafish gastrula, including the neural crest progenitors, are established by a bmp2b/swirl pathway of genes.

A bone morphogenetic protein (BMP) signaling pathway is implicated in dorsoventral patterning in Xenopus. Here we show that three genes in the zebrafish, swirl, snailhouse, and somitabun, function as critical components within a BMP pathway to pattern ventral regions of the embryo. The dorsalized mutant phenotypes of these genes can be rescued by overexpression of bmp4, bmp2b, an activated BMP type I receptor, and the downstream functioning Smad1 gene. Consistent with a function as a BMP ligand, swirl functions cell nonautonomously to specify ventral cell fates. Chromosomal mapping of swirl and cDNA sequence analysis demonstrate that swirl is a mutation in the zebrafish bmp2b gene. Interestingly, our analysis suggests that the previously described nonneural/neural ectodermal interaction specifying the neural crest occurs through a patterning function of swirl/bmp2b during gastrulation. We observe a loss in neural crest progenitors in swirl/bmp2b mutant embryos, while somitabun mutants display an opposite, dramatic expansion of the prospective neural crest. Examination of dorsally and ventrally restricted markers during gastrulation reveals a successive reduction and reciprocal expansion in nonneural and neural ectoderm, respectively, in snailhouse, somitabun, and swirl mutant embryos, with swirl/bmp2b mutants exhibiting almost no nonneural ectoderm. Based on the alterations in tissue-specific gene expression, we propose a model whereby swirl/bmp2b acts as a morphogen to specify different cell types along the dorsoventral axis.

Animals↗
PubMed2006

The repertoire of olfactory C family G protein-coupled receptors in zebrafish: candidate chemosensory receptors for amino acids.

BACKGROUND: Vertebrate odorant receptors comprise at least three types of G protein-coupled receptors (GPCRs): the OR, V1R, and V2R/V2R-like receptors, the latter group belonging to the C family of GPCRs. These receptor families are thought to receive chemosensory information from a wide spectrum of odorant and pheromonal cues that influence critical animal behaviors such as feeding, reproduction and other social interactions. RESULTS: Using genome database mining and other informatics approaches, we identified and characterized the repertoire of 54 intact "V2R-like" olfactory C family GPCRs in the zebrafish. Phylogenetic analysis - which also included a set of 34 C family GPCRs from fugu - places the fish olfactory receptors in three major groups, which are related to but clearly distinct from other C family GPCRs, including the calcium sensing receptor, metabotropic glutamate receptors, GABA-B receptor, T1R taste receptors, and the major group of V2R vomeronasal receptor families. Interestingly, an analysis of sequence conservation and selective pressure in the zebrafish receptors revealed the retention of a conserved sequence motif previously shown to be required for ligand binding in other amino acid receptors. CONCLUSION: Based on our findings, we propose that the repertoire of zebrafish olfactory C family GPCRs has evolved to allow the detection and discrimination of a spectrum of amino acid and/or amino acid-based compounds, which are potent olfactory cues in fish. Furthermore, as the major groups of fish receptors and mammalian V2R receptors appear to have diverged significantly from a common ancestral gene(s), these receptors likely mediate chemosensation of different classes of chemical structures by their respective organisms.

Amino Acid Sequence↗
PubMed2005

Ontogeny and regulation of matrix metalloproteinase activity in the zebrafish embryo by in vitro and in vivo zymography.

Remodeling of the extracellular matrix (ECM) during development, angiogenesis, wound healing, tumor metastasis, and other morphogenetic processes depends on the exquisitely regulated activities of matrix metalloproteinases (MMPs). Yet very little is known about the activity patterns of these proteases in vivo. We have employed fluorescent MMP-substrates, both in vitro and in vivo, to characterize patterns of MMP activity in the zebrafish embryo. Qualitatively similar patterns of degradation are detected using native Type I or Type IV collagen substrates, suggesting that multiple MMPs are being regulated concomitantly. MMP activity is observed primarily in ECM-rich structures predicted to be undergoing active remodeling, such as the perichordal sheath and somite boundaries. Patterns of Type I and Type IV collagen hydrolysis are similar, but not identical in embryos of any given stage. Conventional gelatin zymography shows MMPs present in embryos as early as 3-somites (11 h) and our in vivo assays detect Type IV collagen degradation at somite boundaries as early as 4-somites (11.5 h). However, we are unable to detect significant in vitro activity using homogenates made from embryos prior to Prim-16 (31 h). Mixed lysate assays demonstrate that this is the result of endogenous inhibitors present in early embryos, suggesting a model of matrix remodeling regulated by spatially heterogeneous MMP inhibition.

Animals↗
PubMed2003

Axon fasciculation and differences in midline kinetics between pioneer and follower axons within commissural fascicles.

Early neuronal scaffold development studies suggest that initial neurons and their axons serve as guides for later neurons and their processes. Although this arrangement might aid axon navigation, the specific consequence(s) of such interactions are unknown in vivo. We follow forebrain commissure formation in living zebrafish embryos using timelapse fluorescence microscopy to examine quantitatively commissural axon kinetics at the midline: a place where axon interactions might be important. Although it is commonly accepted that commissural axons slow down at the midline, our data show this is only true for leader axons. Follower axons do not show this behavior. However, when the leading axon is ablated, follower axons change their midline kinetics and behave as leaders. Similarly, contralateral leader axons change their midline kinetics when they grow along the opposite leading axon across the midline. These data suggest a simple model where the level of growth cone exposure to midline cues and presence of other axons as a substrate shape the midline kinetics of commissural axons.

Animals↗
PubMed2005

Developmental expression and nutritional regulation of a zebrafish gene homologous to mammalian microsomal triglyceride transfer protein large subunit.

The microsomal triglyceride transfer protein (MTP) large subunit is required for the assembly and secretion of apolipoprotein B-containing lipoproteins. We have found a zebrafish mtp homologous gene coding a protein with 54% identity with human MTP large subunit with the most conserved regions distributed in the corresponding predicted alpha-helical and C- and A-sheet domains. In situ hybridizations showed that zebrafish mtp transcripts were distributed in the yolk syncytial layer during early embryogenesis and in anterior intestine and liver from 48 hr postfertilization onward. Real-time quantitative RT-PCR confirmed the developmental regulation and tissue-specificity of mtp expression. A significant pretranslational up-regulation of mtp expression was observed in the anterior intestine after feeding. The nutritional regulation of zebrafish mtp expression observed in the anterior intestine supports the notion that this protein, similar to mammalian MTP large subunit, could be a factor implicated directly or indirectly in large lipid droplets accumulation observed in the fish enterocyte after feeding.

Amino Acid Sequence↗
PubMed2006

Development of a zebrafish 4-day embryo-larval bioassay to assess toxicity of chemicals.

A 4-day embryo-larval zebrafish test, from blastula stage to hatching included, was developed. The observations of embryo developmental were made at different development stages, for which morphological, physiological, and behavioral endpoints were selected and quantified for unexposed and exposed embryos. The sensitivity and the ability of these endpoints to inform about mode of action (MoA) were established in testing three model toxicants with well-known toxic effects (propranolol, malathion, cadmium). Lethal, sublethal (heart rate/edema, spontaneous movements, and hatching rate/time disturbance), and teratogenic effects were detected for all the studied compounds. This bioassay allows characterization of impairments at different biological levels: neuromuscular, physiological, morphological, and behavioral, and brings useful information about the toxic MoA of the chemicals on nontarget organisms. In this sense to answers the chemical industries and international organization (EMEA) requirements for the environmental risk assessment of new chemicals and pharmaceuticals.

Animals↗
PubMed1999

An ascidian T-box gene As-T2 is related to the Tbx6 subfamily and is associated with embryonic muscle cell differentiation.

The T-box genes, including Brachyury, encode a novel family of transcription factors that play critical roles in various processes of development, in particular, mesoderm formation in chordate embryos. In the case of the ascidian Halocynthia roretzi, the Brachyury (As-T) is expressed exclusively in notochord cells, whereas another T-box gene (As-T2) is expressed in the muscle cells and in the tip of the tail of tailbud embryos. In a previous study, we suggested that the combined pattern of the spatial expressions of As-T and As-T2 appears to correspond to that of a single vertebrate Brachyury gene (Yasuo et al., Dev Biol 1996;180:773-779). The present molecular phylogenetic analysis suggested that As-T2 is a divergent member of the T-box family with a similarity to the Tbx6 subfamily. Vertebrate members of this subfamily are expressed in the posterior paraxial mesoderm, and the mouse Tbx6 is essential for the specification of posterior somite. To investigate the function of As-T2, we examined an ectopic- and/or overexpression of this gene by injecting synthetic mRNA into fertilized eggs. The results showed that the injection of As-T2 mRNA induced an ectopic expression of muscle-specific myosin heavy-chain gene and actin gene, especially in presumptive epidermal cells. This ectopic muscle-specific expression was accompanied by the partial suppression of an epidermis-specific gene expression. The overexpression of As-T2, however, rarely affected the expression of As-T (Brachyury) and genes that are expressed in the tailbud.

Amino Acid Sequence↗
PubMed2004

Antero-posterior tissue polarity links mesoderm convergent extension to axial patterning.

Remodelling its shape, or morphogenesis, is a fundamental property of living tissue. It underlies much of embryonic development and numerous pathologies. Convergent extension (CE) of the axial mesoderm of vertebrates is an intensively studied model for morphogenetic processes that rely on cell rearrangement. It involves the intercalation of polarized cells perpendicular to the antero-posterior (AP) axis, which narrows and lengthens the tissue. Several genes have been identified that regulate cell behaviour underlying CE in zebrafish and Xenopus. Many of these are homologues of genes that control epithelial planar cell polarity in Drosophila. However, elongation of axial mesoderm must be also coordinated with the pattern of AP tissue specification to generate a normal larval morphology. At present, the long-range control that orients CE with respect to embryonic axes is not understood. Here we show that the chordamesoderm of Xenopus possesses an intrinsic AP polarity that is necessary for CE, functions in parallel to Wnt/planar cell polarity signalling, and determines the direction of tissue elongation. The mechanism that establishes AP polarity involves graded activin-like signalling and directly links mesoderm AP patterning to CE.

Activins↗
PubMed2005

Discovery of a unique Ig heavy-chain isotype (IgT) in rainbow trout: Implications for a distinctive B cell developmental pathway in teleost fish.

During the analysis of Ig superfamily members within the available rainbow trout (Oncorhynchus mykiss) EST gene index, we identified a unique Ig heavy-chain (IgH) isotype. cDNAs encoding this isotype are composed of a typical IgH leader sequence and a VDJ rearranged segment followed by four Ig superfamily C-1 domains represented as either membrane-bound or secretory versions. Because teleost fish were previously thought to encode and express only two IgH isotypes (IgM and IgD) for their humoral immune repertoire, we isolated all three cDNA isotypes from a single homozygous trout (OSU-142) to confirm that all three are indeed independent isotypes. Bioinformatic and phylogenetic analysis indicates that this previously undescribed divergent isotype is restricted to bony fish, thus we have named this isotype "IgT" (tau) for teleost fish. Genomic sequence analysis of an OSU-142 bacterial artificial chromosome (BAC) clone positive for all three IgH isotypes revealed that IgT utilizes the standard rainbow trout V(H) families, but surprisingly, the IgT isotype possesses its own exclusive set of D(H) and J(H) elements for the generation of diversity. The IgT D and J segments and tau constant (C) region genes are located upstream of the D and J elements for IgM, representing a genomic IgH architecture that has not been observed in any other vertebrate class. All three isotypes are primarily expressed in the spleen and pronephros (bone marrow equivalent), and ontogenically, expression of IgT is present 4 d before hatching in developing embryos.

Amino Acid Sequence↗
PubMed2003

A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor.

LDL receptor-related protein 6 (LRP6) is a Wnt coreceptor in the canonical signaling pathway, which plays essential roles in embryonic development. We demonstrate here that wild-type LRP6 forms an inactive dimer through interactions mediated by epidermal growth factor repeat regions within the extracellular domain. A truncated LRP6 comprising its transmembrane and cytoplasmic domains is expressed as a constitutively active monomer whose signaling ability is inhibited by forced dimerization. Conversely, Wnts are shown to activate canonical signaling through LRP6 by inducing an intracellular conformational switch which relieves allosteric inhibition imposed on the intracellular domains. Thus, Wnt canonical signaling through LRP6 establishes a novel mechanism for receptor activation which is opposite to the general paradigm of ligand-induced receptor oligomerization.

Allosteric Site↗
PubMed1997

Noggin acts downstream of Wnt and Sonic Hedgehog to antagonize BMP4 in avian somite patterning.

In the vertebrate embryo, the lateral compartment of the somite gives rise to muscles of the limb and body wall and is patterned in response to lateral-plate-derived BMP4. Activation of the myogenic program distinctive to the medial somite, i.e. relatively immediate development of the epaxial muscle lineage, requires neutralization of this lateral signal. We have analyzed the properties of molecules likely to play a role in opposing lateral somite specification by BMP4. We propose that the BMP4 antagonist Noggin plays an important role in promoting medial somite patterning in vivo. We demonstrate that Noggin expression in the somite is under the control of a neural-tube-derived factor, whose effect can be mimicked experimentally by Wnt1. Wnt1 is appropriately expressed in the neural tube. Furthermore, we show that Sonic Hedgehog is able to activate ectopic expression of Noggin resulting in the blocking of BMP4 specification of the lateral somite. Our results are consistent with a model in which Noggin activation lies downstream of the SHH and Wnt signaling pathways.

Animals↗