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PubMed2026

Microbiota-gut-muscle axis shapes fish muscle texture by regulating collagen synthesis.

BACKGROUND: Increasing studies have emphasized the communication network between the gut microbiome and host organs, revealing that such interactions significantly influence host physiological performances. However, whether a gut-muscle axis exists to regulate muscle quality in animal production is unknown. RESULTS: In two independent cohorts, the muscle hardness of tilapia subjected to a long-term faba bean diet exhibited significant inter-individual variation. RNA-Seq analyses of the high-hardness (H) and low-hardness (L) groups pointed to collagen-based extracellular matrix as a possible factor driving muscle hardness development. Transplantation of gut microbiota from the H donor resulted in enhanced collagen synthesis in gnotobiotic zebrafish. Muscular collagen deposition was featured with an increased abundance of gut Cetobacterium. Gnotobiotic models colonized with live C. somerae exhibited enhanced collagen synthesis. Integrated analyses of microbiome function, bacterial genome, and metabolic profiles identified acetate as a key effector of C. somerae. Acetate incubation upregulated collagen I expression in TGF-β-activated fibroblasts in an acetylation-dependent manner. Mechanistically, acetate promoted the acetylation of SMAD2/3, enhancing its nuclear transport and stability, which ultimately increased collagen expression. An acetate-supplemented feeding experiment corroborated these findings. CONCLUSION: The comprehensive results provided evidences that gut microbes regulated tilapia muscle texture through SMAD2/3 acetylation-driven collagen synthesis. This study expands our understanding of the multifaceted role of the gut-muscle axis in muscle physiology. Furthermore, our findings highlight that targeting gut microbiota and the downstream collagen synthesis pathway could be promising for manipulating muscle quality in animal production. Video Abstract.

Animals↗
PubMed2006

A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration.

Zebrafish possess a unique yet poorly understood capacity for cardiac regeneration. Here, we show that regeneration proceeds through two coordinated stages following resection of the ventricular apex. First a blastema is formed, comprised of progenitor cells that express precardiac markers, undergo differentiation, and proliferate. Second, epicardial tissue surrounding both cardiac chambers induces developmental markers and rapidly expands, creating a new epithelial cover for the exposed myocardium. A subpopulation of these epicardial cells undergoes epithelial-to-mesenchymal transition (EMT), invades the wound, and provides new vasculature to regenerating muscle. During regeneration, the ligand fgf17b is induced in myocardium, while receptors fgfr2 and fgfr4 are induced in adjacent epicardial-derived cells. When fibroblast growth factors (Fgf) signaling is experimentally blocked by expression of a dominant-negative Fgf receptor, epicardial EMT and coronary neovascularization fail, prematurely arresting regeneration. Our findings reveal injury responses by myocardial and epicardial tissues that collaborate in an Fgf-dependent manner to achieve cardiac regeneration.

Animals↗
PubMed2004

Continuous tooth replacement: the possible involvement of epithelial stem cells.

Epithelial stem cells have been identified in integumental structures such as hairs and continuously growing teeth of various rodents, and in the gut. Here we propose the involvement of epithelial stem cells in the continuous tooth replacement that characterizes non-mammalian vertebrates, as exemplified by the zebrafish. Arguments are based on morphological observations of tooth renewal in the zebrafish and on the similarities between molecular control of hair and tooth formation. Dissection of the molecular cascades underlying the regulation of the epithelial stem cell niche might open perspectives for new regenerative treatment strategies in clinical dentistry.

Animals↗
PubMed2006

En bloc duplications, mutation rates, and densities of amino acid changes clarify the evolution of vertebrate alpha-1,3/4-fucosyltransferases.

Numerous vertebrates have four alpha-1,3/4-fucosyltransferase genes (FUT9, FUT7, FUT4, and FUT Lewis) belonging to the same family. Until now, studies on the evolution of this family have mainly focused on Lewis genes but how the other alpha-1,3/4-fucosyltransferases have emerged from a common ancestor is not well known. In order to define the respective roles of duplications and mutations, we have compared amino acid sequences representative of bony fish (Takifugu rubripes), amphibians (Xenopus laevis), birds (Gallus gallus), and mammals (Bos taurus). The FUT tree has two fundamental branches, each split into two subfamilies. We found evidence for two duplication events, dated around 710-760 Myr and 590-640 Myr, respectively, compatible with the hypothesis of two rounds of whole genome duplications in chordate genomes, before the emergence of bony vertebrates. Based on the Homo sapiens (human) physical map, we identified blocks of paralogues belonging to regions of FUT9 (6q16), FUT4 (11q21), FUT7 (9q34), and FUT Lewis (19p13) and to a region on HSA1p that is devoid of any FUT. In zebrafish (Danio rerio), an orthologue region of HSA1 harbors an FUT9 specific to bony fish, showing that duplications are not restricted to a single FUT gene but involve blocks of paralogues. In addition, sets of genes within each block clarify the order of duplication events and, as a result, the order of alpha-1,3/4-fucosyltransferase gene emergence. We have also determined the mutation rates and the density of amino acid changes along protein sequences in each alpha-1,3/4-fucosyltransferase subfamily during the main vertebrate transitions. After the emergence of tetrapods, the mutation rate of FUT9 decreased dramatically, suggesting the early acquisition of a crucial fucosyltransferase activity in the first stages of development. The FUT7 mutation rate, which in tetrapod ancestors is about half that in amniote ancestors, may be related to the role of this gene in immune systems. In contrast to other subfamilies, we found a constant mutation rate in FUT Lewis and a rather homogeneous amino acid density change, independently of the vertebrate transition, suggesting that hitherto Lewis epitopes have dispensable functions.

Ambystoma↗
PubMed1997

Localized calcium transients accompany furrow positioning, propagation, and deepening during the early cleavage period of zebrafish embryos.

Through the injection of f-aequorin (a calcium-specific luminescent reporter) and the use of an imaging photon detector, we see a distinct localized elevation of intracellular calcium that accompanies the appearance of the first furrow arc at the blastodisc surface: the furrow positioning signal. As the leading edges of the arc progress outward toward the margins of the blastodisc, they are accompanied by two subsurface slow calcium waves moving at about 0.2 micron/s: the furrow propagation signal. As these wave fronts approach the edge of the blastodisc, another calcium signal arises in the central region where the positioning signal originally appeared. Like the propagation signal, it extends outward to the margins of the blastodisc, but in this case it also moves downward, accompanying the deepening process that separates the daughter cells: the furrow deepening signal. Both of these furrow deepening progressions move at around 0.1 to 0.2 micron/s. The deepening signal begins to diminish from the center outward, returning to precleavage resting levels on completion of cytokinesis. The signaling sequence is repeated during the second cell division cycle. These localized transients do not require external calcium and they can be dissipated after they have begun by introducing calcium shuttle buffers, resulting in furrow delocalization and regression. They also occur in parthenogenetically activated eggs in which, in an attenuated form, they accompany abortive cleavages.

Aequorin↗
PubMed2004

Skin development in bony fish with particular emphasis on collagen deposition in the dermis of the zebrafish (Danio rerio).

The first part of this article is a review of the current status of knowledge of the fish skin, with particular attention to its development. In the second part we present original results obtained in zebrafish (Danio rerio), with particular emphasis on the deposition and organisation of the dermal collagenous stroma. Using a series of zebrafish specimens aged between 15 hours postfertilization (hpf) and 4.5 years old, we have combined Transmission Electron Microscopy (TEM) observations and in situ hybridisation using type I collagen a2 chain (Col1a2) probe. Collagen fibrils, with a diameter of 22 nm, appear first in an acellular subepidermal space at 24 hpf, are first all oriented in the same direction, and form the primary dermal stroma. Subsequently, three events occur. (1) From 5-7 days pf (dpf) onwards the collagen fibrils self-organise into several lamellae arranged in a plywood-like structure, starting in the upper layers and progressing throughout the entire thickness of the dermis. (2) At 20-26 dpf, fibroblasts of unknown origin progressively invade the acellular collagenous stroma, some of them accumulating below the epidermis. (3) Concomitant with the invasion of fibroblasts, the collagen fibrils increase progressively in diameter to reach 160 nm towards the end of the fish life. In situ hybridisation experiments reveal that, between 24 and 48 hpf, the collagen matrix is produced by the epidermis only. From 72 hpf to 20-26 dpf, both the basal epidermal cells and the dermal cells bordering the deep region of the dermis are involved in the production of collagen. When the fibroblasts invade the plywood-like structure, the epidermal cells progressively cease to synthesise collagen, which from this point is produced only by the fibroblasts. This suggests that the fibroblasts secrete a still unidentified signalling molecule that downregulates collagen production by the epidermis.

Animals↗
PubMed2026

Genome-wide association and multi-omics functional screens reveal the genetic architecture of foveal development.

Foveal hypoplasia causes visual impairment across congenital eye disorders, yet the genetic programmes governing foveal development remain poorly characterised and no tractable model exists for foveal disease. In the first genome-wide association study of foveal hypoplasia, we identified 42 sentinel variants mapping to 54 effector genes supported by ≥ 2 criteria from a variant-to-gene framework incorporating developmental multi-omics. Disruption of six effector genes using mutant lines and CRISPR knockouts in the zebrafish high acuity zone recapitulates structural, functional, and ultrastructural hallmarks of foveal hypoplasia, establishing the first vertebrate disease model. Integration with human foetal single-cell and spatial transcriptomics reveals two temporal waves of effector gene expression and identifies Müller glia as critical mediators of foveal patterning. Phenome-wide analyses reveal foveal variants are pleiotropic with refractive, lenticular, and metabolic traits, connecting foveal development to anterior segment and systemic disease biology. These findings should inform mechanistic studies of macular disease.

Journal Article↗
PubMed2004

Genetic approaches to disease and regeneration.

Cardiovascular disease is largely a consequence of coronary artery blockage through excessive proliferation of smooth muscle cells. It in turn leads to myocardial infarction and permanent and functionally devastating tissue damage to the heart wall. Our studies have revealed that elastin is a primary player in maintaining vascular smooth muscle cells in their dormant state and thus may be a useful therapeutic in vascular disease. By studying zebrafish, which unlike humans, can repair damage to heart muscle, we have begun to uncover some of the genes that seem necessary to undertake the de-differentiation steps that currently fail and prevent the formation of new proliferating cardiomyocytes at the site of damage in a mammalian heart.

Animals↗
PubMed2004

Organization of cardiac chamber progenitors in the zebrafish blastula.

Organogenesis requires the specification of a variety of cell types and the organization of these cells into a particular three-dimensional configuration. The embryonic vertebrate heart is organized into two major chambers, the ventricle and atrium, each consisting of two tissue layers, the myocardium and endocardium. The cellular and molecular mechanisms responsible for the separation of ventricular and atrial lineages are not well understood. To test models of cardiac chamber specification, we generated a high-resolution fate map of cardiac chamber progenitors in the zebrafish embryo at 40% epiboly, a stage prior to the initiation of gastrulation. Our map reveals a distinct spatial organization of myocardial progenitors: ventricular myocardial progenitors are positioned closer to the margin and to the dorsal midline than are atrial myocardial progenitors. By contrast, ventricular and atrial endocardial progenitors are not spatially organized at this stage. The relative orientations of ventricular and atrial myocardial progenitors before and after gastrulation suggest orderly movements of these populations. Furthermore, the initial positions of myocardial progenitors at 40% epiboly indicate that signals residing at the embryonic margin could influence chamber fate assignment. Indeed, via fate mapping, we demonstrate that Nodal signaling promotes ventricular fate specification near the margin, thereby playing an important early role during myocardial patterning.

Animals↗
PubMed2004

Touchtone promotes survival of embryonic melanophores in zebrafish.

An outstanding problem in the study of vertebrate development is the identification of the genes that direct neural crest precursor cells to adopt and maintain specific differentiated cell fates. In an effort to identify such genes, we have carried out a mutagenesis screen in zebrafish and isolated mutants that lack neural crest-derived melanophores. In this manuscript we describe the phenotype of one such mutant, touchtone(b722) (tct), and the map position of the gene it defines. Analysis of expression of dopachrome tautomerase (dct) and microphthalmia (mitfa) suggests that melanophore precursors are specified normally in homozygous tct mutants. However, differentiated melanophores are pale, small, and about half of them have disappeared by 48 h of development, apparently by cell death. We show that melanophores require Tct function cell autonomously. Signals from the receptor tyrosine kinase receptor C-kit are essential for survival of melanophores in zebrafish and mammals. However, differences in the phenotypes of tct and c-kit homozygous mutants, and an absence of interaction between c-kit and tct heterozygotes, suggest that Tct functions independently of the C-kit pathway. Other neural crest derivatives, including other pigment cell types, appear normal in tct mutants. Interestingly, tct mutant embryos undergo a temporary period of near complete paralyzis during the second day of development, although markers of axons of motor and sensory neurons look normal in this period. A fraction of tct(b722) mutants survive to adulthood, but mutant adults are small, indicating a role for Tct in post-larval growth. The tct gene maps to a small interval near a telomere of chromosome 18. Thus, we have identified a zebrafish gene that when mutated produces semi-viable offspring and that may serve as a model of human diseases that have both pigmentation and neurological symptoms.

Animals↗
PubMed2005

Mutations in connexin43 (GJA1) perturb bone growth in zebrafish fins.

Mechanisms that regulate the size and shape of bony structures are largely unknown. The molecular identification of the fin length mutant short fin (sof), which causes defects in the length of bony fin ray segments, may provide insights regarding the regulation of bone growth. In this report, we demonstrate that the sof phenotype is caused by mutations in the connexin43 (cx43) gene. This conclusion is supported by genetic mapping, reduced expression of cx43 in the original sof allele (sofb123), identification of missense mutations in three ENU-induced alleles, and by demonstration of partially abrogated cx43 function in sofb123 embryos. Expression of cx43 was identified in cells flanking the germinal region of newly growing segments as well as in the osteoblasts at segment boundaries. This pattern of cx43 expression in cells lateral to new segment growth is consistent with a model where cx43-expressing cells represent a biological ruler that measures segment size. This report identifies the first gene identification for a fin length mutation (sof) as well as the first connexin mutations in zebrafish, and therefore reveals a critical role for local cell-cell communication in the regulation of bone size and growth.

Alleles↗
PubMed2000

Development of spontaneous glycinergic currents in the Mauthner neuron of the zebrafish embryo.

We used whole cell and outside-out patch-clamp techniques with reticulospinal Mauthner neurons of zebrafish embryos to investigate the developmental changes in the properties of glycinergic synaptic currents in vivo from the onset of synaptogenesis. Miniature inhibitory postsynaptic currents (mIPSCs) were isolated and recorded in the presence of TTX (1 microM), kynurenic acid (1 mM), and bicuculline (10 microM) and were found to be sensitive to strychnine (1 microM). The mIPSCs were first observed in 26-29 h postfertilization (hpf) embryos at a very low frequency of approximately 0.04 Hz, which increased to approximately 0.5 Hz by 30-40 hpf, and was approximately 10 Hz in newly hatched (>50 hpf) larvae, indicating an accelerated increase in synaptic activity. At all embryonic stages, the amplitudes of the mIPSCs were variable but their means were similar ( approximately 100 pA), suggesting rapid formation of the postsynaptic matrix. The 20-80% rise times of mIPSCs in embryos were longer (0.6-1.2 ms) than in larvae (approximately 0.3 ms), likely due to slower diffusion of glycine at the younger, immature synapses. The mIPSCs decayed with biexponential (tau(off1) and tau(off2)) time courses with a half-width in 26-29 hpf embryos that was longer and more variable than in older embryos and larvae. In 26- to 29-hpf embryos, tau(off1) was approximately 15 ms and tau(off2) was approximately 60 ms, representing events of intermediate duration; but occasionally long mIPSCs were observed in some cells where tau(off1) was approximately 40 ms and tau(off2) was approximately 160 ms. In 30-40 hpf embryos, the events were faster, with tau(off1) approximately 9 ms and tau(off2) approximately 40 ms, and in larvae, events declined somewhat further to tau(off1) approximately 4 ms and tau(off2) approximately 30 ms. Point-per-point amplitude histograms of the decay of synaptic events at all stages resulted in the detection of similar single channel conductances estimated as approximately 45 pS, indicating the presence of heteromeric glycine receptors (GlyRs) from the onset of synaptogenesis. Fast-flow (1 ms) application of a saturating concentration of glycine (3-10 mM) to outside-out patches obtained at 26-29 hpf revealed GlyR currents that decayed biexponentially with time constants resembling the values found for intermediate and long mIPSCs; by 30-40 hpf, the GlyR currents resembled fast mIPSCs. These observations indicate that channel kinetics limited the mIPSC duration. Our data suggest that glycinergic mIPSCs result from the activation of a mixture of fast and slow GlyR subtypes, the properties and proportion of which determine the decay of the synaptic events in the embryos.

Animals↗
PubMed2006

Vhnf1 acts downstream of Bmp, Fgf, and RA signals to regulate endocrine beta cell development in zebrafish.

Bmp, Fgf, and retinoic acid (RA) signals have been implicated as regulators of pancreas development. However, the integration of these signaling pathways in vivo is not fully understood. Variant hnf1 (Vhnf1) is a transcription factor involved in pancreas, liver, and kidney development and its mutation in zebrafish causes underdeveloped pancreas and liver. We investigated the signaling pathways that regulate vhnf1 expression during pancreas development. First, we showed that Bmp activity is required for vhnf1 expression in the endoderm. In chordin (a Bmp antagonist) morpholino (MO)-injected embryos, vhnf1 expression in endoderm and in endocrine beta cells is expanded. On the other hand, in alk8 (a type I TGFbeta receptor) MO-injected embryos, vhnf1 expression in the endoderm is significantly reduced. Second, we showed that Fgf signaling participates in regulation of pancreas development through the vhnf1 pathway. Third, we demonstrated that RA fails to rescue reduction of insulin expression in vhnf1 mutants, whereas overexpression of vhnf1 restores insulin expression that is repressed by treatment with a RA receptor inhibitor. And finally, we revealed that both Bmp and Fgf signals act genetically upstream of RA in directing pancreas development. Taken together, our data establish that vhnf1 acts downstream of the signaling pathways of RA, Bmp, and Fgf to regulate pancreas development in zebrafish.

Animals↗
PubMed2005

Identification of a new pebp2alphaA2 isoform from zebrafish runx2 capable of inducing osteocalcin gene expression in vitro.

UNLABELLED: The zebrafish runx2b transcription factor is an ortholog of RUNX2 and is highly conserved at the structural level. The runx2b pebp2alphaA2 isoform induces osteocalcin gene expression by binding to a specific region of the promoter and seems to have been selectively conserved in the teleost lineage. INTRODUCTION: RUNX2 (also known as CBFA1/Osf2/AML3/PEBP2alphaA) is a transcription factor essential for bone formation in mammals, as well as for osteoblast and chondrocyte differentiation, through regulation of expression of several bone- and cartilage-related genes. Since its discovery, Runx2 has been the subject of intense studies, mainly focused in unveiling regulatory targets of this transcription factor in high vertebrates. However, no single study has been published addressing the role of Runx2 in bone metabolism of low vertebrates. While analyzing the zebrafish (Danio rerio) runx2 gene, we identified the presence of two orthologs of RUNX2, which we named runx2a and runx2b and cloned a pebp2alphaA-like transcript of the runx2b gene, which we named pebp2alphaA2. MATERIALS AND METHODS: Zebrafish runx2b gene and cDNA were isolated by RT-PCR and sequence data mining. The 3D structure of runx2b runt domain was modeled using mouse Runx1 runt as template. The regulatory effect of pebp2alphaA2 on osteocalcin expression was analyzed by transient co-transfection experiments using a luciferase reporter gene. Phylogenetic analysis of available Runx sequences was performed with TREE_PUZZLE 5.2. and MrBayes. RESULTS AND CONCLUSIONS: We showed that the runx2b gene structure is highly conserved between mammals and fish. Zebrafish runx2b has two promoter regions separated by a large intron. Sequence analysis suggested that the runx2b gene encodes three distinct isoforms, by a combination of alternative splicing and differential promoter activation, as described for the human gene. We have cloned a pebp2alphaA-like transcript of the runx2b gene, which we named pebp2alphaA2, and showed its high degree of sequence similarity with the mammalian pebp2alphaA. The cloned zebrafish osteocalcin promoter was found to contain three putative runx2-binding elements, and one of them, located at -221 from the ATG, was capable of mediating pebp2alphaA2 transactivation. In addition, cross-species transactivation was also confirmed because the mouse Cbfa1 was able to induce the zebrafish osteocalcin promoter, whereas the zebrafish pebp2alphaA2 activated the murine osteocalcin promoter. These results are consistent with the high degree of evolutionary conservation of these proteins. The 3D structure of the runx2b runt domain was modeled based on the runt domain of mouse Runx1. Results show a high degree of similarity in the 3D configuration of the DNA binding regions from both domains, with significant differences only observed in non-DNA binding regions or in DNA-binding regions known to accommodate considerable structure flexibility. Phylogenetic analysis was used to clarify the relationship between the isoforms of each of the two zebrafish Runx2 orthologs and other Runx proteins. Both zebrafish runx2 genes clustered with other Runx2 sequences. The duplication event seemed, however, to be so old that, whereas Runx2b clearly clusters with the other fish sequences, it is unclear whether Runx2a clusters with Runx2 from higher vertebrates or from other fish.

Amino Acid Sequence↗
PubMed2002

Vitellogenin induction by 17beta-estradiol and 17alpha-ethinylestradiol in male zebrafish (Danio rerio).

Adult male zebrafish (Danio rerio) were exposed to 17beta-estradiol (E2) or 17alpha-ethinylestradiol (EE2) in flow-through systems for 8 days. This was done to compare the sensitivity of the estrogen inducible vitellogenin (Vtg) biomarker system of this proposed OECD test guideline species to other relevant test species. Vtg was quantified in whole body homogenate by a species-specific ELISA. Actual water concentrations of E2 and EE2 were quantified by LC-MS, with detection limits of 1.0 and 0.6 ng/l, respectively. Vtg induction (LOEC) occurred in whole body homogenate at actual water concentrations of 21 ng E2/l and 3.0 ng EE2/l, respectively. As an alternative to the ANOVA approach, the relationship between the percentage of responding fish (Vtg) and the external E2 or EE2 concentration was determined by logistic regression analysis. Based on the regression analysis, EC-values could be determined: EC10, EC50 and EC90 were 15.4, 41.2 and 67.1 ng E2/l, respectively and 0.92, 2.51 and 4.09 ng EE2/l, respectively. Comparisons of these response limits to corresponding values for rainbow trout (Oncorhynchus mykiss), fathead minnow (Pimephales promelas) and Japanese medaka (Oryzias latipes) revealed the zebrafish as a sensitive test species.

Animals↗
PubMed1998

Differential expression of voltage-gated K+ and Ca2+ currents in bipolar cells in the zebrafish retinal slice.

Whole-cell voltage-gated currents were recorded from bipolar cells in the zebrafish retinal slice. Two physiological populations of bipolar cells were identified. In the first, depolarizing voltage steps elicited a rapidly activating A-current that reached peak amplitude < or = 5 ms of step onset. IA was antagonized by external tetraethylammonium or 4-aminopyridine, and by intracellular caesium. The second population expressed a delayed rectifying potassium current (IK) that reached peak amplitude > or = 10 ms after step onset and did not inactivate. IK was antagonized by internal caesium and external tetraethylammonium. Bipolar cells expressing IK also expressed a time-dependent h-current at membrane potentials < -50 mV. Ih was sensitive to external caesium and barium, and was also reduced by Na+-free Ringer. In both groups, a calcium current (ICa) and a calcium-dependent potassium current (IK(Ca)) were identified. Depolarizing voltage steps > -50 mV activated ICa, which reached peak amplitude between -20 and -10 mV. ICa was eliminated in Ca+2-free Ringer and blocked by cadmium and cobalt, but not tetrodotoxin. In most cells, Ica was transient, activating rapidly at -50 mV. This current was antagonized by nickel. The remaining bipolar cells expressed a nifedipine-sensitive sustained current that activated between -40 and -30 mV, with both slower kinetics and smaller amplitude than transient ICa. IK(Ca) was elicited by membrane depolarizations > -20 mV. Bipolar cells in the zebrafish retinal slice preparation express an array of voltage-gated currents which contribute to non-linear I-V characteristics. The zebrafish retinal slice preparation is well-suited to patch clamp analyses of membrane mechanisms and provides a suitable model for studying genetic defects in visual system development.

Animals↗