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PubMed2002

FGF3 and FGF8 mediate a rhombomere 4 signaling activity in the zebrafish hindbrain.

The segmentation of the vertebrate hindbrain into rhombomeres is highly conserved, but how early hindbrain patterning is established is not well understood. We show that rhombomere 4 (r4) functions as an early-differentiating signaling center in the zebrafish hindbrain. Time-lapse analyses of zebrafish hindbrain development show that r4 forms first and hindbrain neuronal differentiation occurs first in r4. Two signaling molecules, FGF3 and FGF8, which are both expressed early in r4, are together required for the development of rhombomeres adjacent to r4, particularly r5 and r6. Transplantation of r4 cells can induce expression of r5/r6 markers, as can misexpression of either FGF3 or FGF8. Genetic mosaic analyses also support a role for FGF signaling acting from r4. Taken together, our findings demonstrate a crucial role for FGF-mediated inter-rhombomere signaling in promoting early hindbrain patterning and underscore the significance of organizing centers in patterning the vertebrate neural plate.

Animals↗

PubMed2026

Granuloma dual RNA-seq reveals composite transcriptional programs driven by neutrophils and necrosis within tuberculous granulomas.

Mycobacterial granulomas lie at the center of tuberculosis (TB) pathogenesis and represent a unique niche where infecting bacteria survive under nutrient-restricted conditions and in the face of a host immune response. The granuloma's necrotic core, where bacteria reside extracellularly in humans, is difficult to assess in many experimentally tractable models. Here, using necrotic mycobacterial granulomas in adult zebrafish, we develop dual RNA sequencing (RNA-seq) across different host genotypes to identify the transcriptional alterations that enable bacteria to survive within this key microenvironment. Using pharmacological and genetic interventions, we find that neutrophils within mature, necrotic granulomas promote bacterial growth, in part through up-regulation of the bacterial devR regulon. We identify conserved suites of bacterial transcriptional programs induced only in the context of this unique necrotic extracellular niche, including bacterial modules related to K+ transport and rpf genes. Analysis of Mycobacterium tuberculosis strains across diverse lineages and human populations suggests that granuloma-specific transcriptional modules are targets for bacterial genetic adaptation in the context of human infection.

Animals↗

PubMed2006

Agrin is required for posterior development and motor axon outgrowth and branching in embryonic zebrafish.

Although recent studies have extended our understanding of agrin's function during development, its function in the central nervous system (CNS) is not clearly understood. To address this question, zebrafish agrin was identified and characterized. Zebrafish agrin is expressed in the developing CNS and in nonneural structures such as somites and notochord. In agrin morphant embryos, acetylcholine receptor (AChR) cluster number and size on muscle fibers at the choice point were unaffected, whereas AChR clusters on muscle fibers in the dorsal and ventral regions of the myotome were reduced or absent. Defects in the axon outgrowth by primary motor neurons, subpopulations of branchiomotor neurons, and Rohon-Beard sensory neurons were also observed, which included truncation of axons and increased branching of motor axons. Moreover, agrin morphants exhibit significantly inhibited tail development in a dose-dependent manner, as well as defects in the formation of the midbrain-hindbrain boundary and reduced size of eyes and otic vesicles. Together these results show that agrin plays an important role in both peripheral and CNS development and also modulates posterior development in zebrafish.

Agrin↗

PubMed2005

Cardiac performance in the zebrafish breakdance mutant.

In the Tubingen screen a breakdance mutant of zebrafish (bre) was described as an arrhythmia, in which the ventricle beats only with every second atrial contraction (2:1 rhythm). Surprisingly, a careful analysis of the effect of the breakdance mutation on cardiac performance of the zebrafish during development between 3 d.p.f. and 14 d.p.f revealed that homozygous bre mutants did not always show the 2:1 rhythm. Cardiac activity was continuously recorded for a period of 20 min in each larva, and during this period we observed that heart rate randomly switched between the 2:1 rhythm and a 1:1 rhythm. Furthermore, at 28 degrees C and at 31 degrees C the expression of the 2:1 rhythm decreased with development. At 31 degrees C this was in part due to a significantly reduced survival rate of mutants beyond 4 d.p.f. Besides development, temperature had a marked effect on the expression of the 2:1 rhythm, and during the first days of development the expression of the 2:1 rhythm was significantly higher at elevated incubation temperatures. By contrast, in the 2:1 beating heart ventricular contraction rate was about 80 beats min(-1) throughout development irrespective of the temperature, and even in the 1:1 rhythm mutants showed a significant bradycardia at all three temperatures (25 degrees C, 28 degrees C or 31 degrees C). Compared to wild-type animals, cardiac output was significantly lower in bre mutants. Pressure traces recorded in the ventricle of mutants revealed a prolonged relaxation phase, indicating that the second pacemaker current could not be conveyed to the ventricle (AV-block). This phenotype is comparable to the human Long QT Syndrome, an arrhythmia caused by a modification of an ion channel involved in cardiac repolarization. The bradycardia and the modified temperature sensitivity of heart rate suggested that the activity of the pacemaker cells was also affected by this mutation.

Animals↗

PubMed2006

Prdm1 acts downstream of a sequential RA, Wnt and Fgf signaling cascade during zebrafish forelimb induction.

Vertebrate limb induction is triggered in the lateral plate mesoderm (LPM) by a cascade of signaling events originating in the axial mesoderm. While it is known that Fgf, Wnt and retinoic acid (RA) signals are involved in this cascade, their precise regulatory hierarchy has not been determined in any species. tbx5 is the earliest gene expressed in the limb bud mesenchyme. Recently, another transcription factor, Prdm1, has been shown to be crucial for zebrafish forelimb development. Here, we show that Prdm1 is downstream of RA, Wnt2b and Tbx5 activity. We find that RA activity, but not Fgf signaling, is necessary for wnt2b expression. Fgf signaling is required for prdm1 expression in the fin bud, but is not necessary for the initiation of tbx5 expression. We propose a model in which RA signaling from the somitic mesoderm leads to activation of wnt2b expression in the intermediate mesoderm, which then signals to the LPM to trigger tbx5 expression. tbx5 is required for Fgf signaling in the limb bud leading to activation of prdm1 expression, which in turn is required for downstream activation of fgf10 expression.

Animals↗

PubMed2001

Gli2 mediation of hedgehog signals in slow muscle induction in zebrafish.

Zebrafish skeletal muscles are composed of two major types of muscle fibers, broadly classified as fast or slow fibers. Recent studies have demonstrated that members of the Hedgehog (Hh) family induce the formation of slow muscle fibers. Hedgehog signals are secreted proteins that function through the transcription factor Glis. We report here the characterization of a zebrafish Gli2 expression in slow and fast muscle cells and the study of the roles of Hedgehogs and Gli2 in zebrafish muscle development using two mutant strains; sonic-you (syu) and you-too (yot), respective for sonic hedgehog (shh) and Gli2 mutation. We have demonstrated that Shh and Gli2 mutation causes similar defects in slow muscle formation. There is, however, a difference in the degree of defect between these two mutants. In yot mutant embryos, development of slow muscles was completely blocked, whereas in syu mutant embryos, a small number of slow muscle cells could still form, suggesting that other Hhs were also involved in slow muscle induction. Induction of slow muscles by other Hhs appeared to require Gli2, because ectopic expression of Echidna hedgehog (Ehh) and Tiggy-winkle hedgehog (Twhh) failed to induce slow muscles in yot mutant embryos. Together, these data suggest that further Hhs, other than Shh, are also involved in the induction and differentiation of slow muscle cells and that Gli2 is required by Shh, Twhh, and Ehh, thus playing a key role in the induction and differentiation of slow muscle cells.

Animals↗

PubMed2006

Effects of larval-juvenile treatment with perchlorate and co-treatment with thyroxine on zebrafish sex ratios.

The objective of this study was to determine the effect of larval-juvenile exposure to perchlorate, a thyroid hormone synthesis inhibitor, on the establishment of gonadal sex ratios in zebrafish. Zebrafish were exposed to untreated water or water containing perchlorate at 100 or 250 ppm for a period of 30 days starting at 3 days postfertilization (dpf). Recovery treatments consisted of a combination of perchlorate and exogenous thyroxine (T4; 10 nM). Thyroid histology was assessed at the end of the treatment period (33 dpf), and gonadal histology and sex ratios were determined in fish that were allowed an additional 10-day period of growth in untreated water. As expected, exposure to perchlorate caused changes in thyroid histology consistent with hypothyroidism and these effects were reversed by co-treatment with exogenous T4. Perchlorate did not affect fish survival but co-treatment with T4 induced higher mortality. However, relative to the corresponding perchlorate concentration, co-treatment with T4 caused increased mortality only at a perchlorate concentration of 100 ppm. Perchlorate alone or in the presence of T4 suppressed body length at 43 dpf relative to control values. Perchlorate exposure skewed the sex ratio toward female in a concentration-dependent manner, and co-treatment with T4 not only blocked the feminizing effect of perchlorate but also overcompensated by skewing the sex ratio towards male. Moreover, co-treatment with T4 advanced the onset of spermatogenesis in males. There was no clear association between sex ratios and larval survival or growth. We conclude that endogenous thyroid hormone plays a role in the establishment of gonadal sex phenotype during early development in zebrafish.

Age Factors↗

PubMed2003

MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limb.

The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol-3-OH kinase (PI3K)/Akt pathways are involved in the regulatory mechanisms of several cellular processes including proliferation, differentiation and apoptosis. Here we show that during chick, mouse and zebrafish limb/fin development, a known MAPK/ERK regulator, Mkp3, is induced in the mesenchyme by fibroblast growth factor 8 (FGF8) signalling, through the PI3K/Akt pathway. This correlates with a high level of phosphorylated ERK in the apical ectodermal ridge (AER), where Mkp3 expression is excluded. Conversely, phosphorylated Akt is detected only in the mesenchyme. Constitutively active Mek1, as well as the downregulation of Mkp3 by small interfering RNA (siRNA), induced apoptosis in the mesenchyme. This suggests that MKP3 has a key role in mediating the proliferative, anti-apoptotic signalling of AER-derived FGF8.

Animals↗

PubMed1991

A pioneering growth cone in the embryonic zebrafish brain.

During development of the nervous system, growth cones navigate very precisely to their appropriate, often distant, targets. In insects, the task of establishing the earliest pathways is accomplished by a small number of neurons, termed pioneers. These neurons have axons that lay down an early scaffold, which provides a substrate for many later-developing axons. Here we show that a similar type of cell exists in the embryonic vertebrate brain. Using light- and electron-microscopic techniques we have examined the formation of one of the earliest tracts in the zebrafish brain. We find that it is pioneered at a precise time by the growth cone of a single neuron present in a predictable location. These observations show a fundamental similarity in the establishment of axonal pathways in the central nervous systems of both invertebrates and vertebrates.

Animals↗

PubMed2002

spiel ohne grenzen/pou2 is required for zebrafish hindbrain segmentation.

Segmentation of the vertebrate hindbrain leads to the formation of a series of rhombomeres with distinct identities. In mouse, Krox20 and kreisler play important roles in specifying distinct rhombomeres and in controlling segmental identity by directly regulating rhombomere-specific expression of Hox genes. We show that spiel ohne grenzen (spg) zebrafish mutants develop rhombomeric territories that are abnormal in both size and shape. Rhombomere boundaries are malpositioned or absent and the segmental pattern of neuronal differentiation is perturbed. Segment-specific expression of hoxa2, hoxb2 and hoxb3 is severely affected during initial stages of hindbrain development in spg mutants and the establishment of krx20 (Krox20 ortholog) and valentino (val; kreisler ortholog) expression is impaired. spg mutants carry loss-of-function mutations in the pou2 gene. pou2 is expressed at high levels in the hindbrain primordium of wild-type embryos prior to activation of krx20 and val. Widespread overexpression of Pou2 can rescue the segmental krx20 and val domains in spg mutants, but does not induce ectopic expression of these genes. This suggests that spg/pou2 acts in a permissive manner and is essential for normal expression of krx20 and val. We propose that spg/pou2 is an essential component of the regulatory cascade controlling hindbrain segmentation and acts before krx20 and val in the establishment of rhombomere precursor territories.

Animals↗

PubMed2005

NO as a mediator during the early development of the cardiovascular system in the zebrafish.

As a general pattern innervation of the cardiovascular system appears late during development in vertebrate embryos, and cardiovascular control may be achieved by hormonal activity in early stages. However, very little is known about the onset of NO-responsiveness during development, which in adult vertebrates is known to play a key function in many physiological processes such as control of vascular tone, neurotransmission, macrophage activity, and angiogenesis. Analysis of the effect of NO on the cardiovascular system in zebrafish (Danio rerio) embryos and larvae revealed almost no effect on cardiac activity during chronic exposure to NO-producing chemicals, whereas vascular reactivity was observed in veins and arteries of the zebrafish in early developmental stages (5-6 days post fertilization). Chronic exposure also modified the development of the vascular system. The presence of an NO donor (sodium nitroprusside) did not change the patterning of the vascular bed, but it induced an earlier appearance of some blood vessels in the trunk region of the zebrafish larvae. The data reveal that NO plays an important role in the development of the cardiovascular system and in the ontogeny of the cardiovascular control system in fish.

Animals↗

PubMed2006

Modeling human muscle disease in zebrafish.

Zebrafish reproduce in large quantities, grow rapidly, and are transparent early in development. For these reasons, zebrafish have been used extensively to model vertebrate development and disease. Like mammals, zebrafish express dystrophin and many of its associated proteins early in development and these proteins have been shown to be vital for zebrafish muscle stability. In dystrophin-null zebrafish, muscle degeneration becomes apparent as early as 3 days post-fertilization (dpf) making the zebrafish an excellent organism for large-scale screens to identify other genes involved in the disease process or drugs capable of correcting the disease phenotype. Being transparent, developing zebrafish are also an ideal experimental model for monitoring the fate of labeled transplanted cells. Although zebrafish dystrophy models are not meant to replace existing mammalian models of disease, experiments requiring large numbers of animals may be best performed in zebrafish. Results garnered from using this model could lead to a better understanding of the pathogenesis of the muscular dystrophies and the development of future therapies.

Animals↗

PubMed2001

Zebrafish fgf3 and fgf8 encode redundant functions required for otic placode induction.

Members of the fibroblast growth factor (FGF) family of peptide ligands have been implicated in otic placode induction in several vertebrate species. Here, we have functionally analyzed the roles of fgf3 and fgf8 in zebrafish otic development. The role of fgf8 was assessed by analyzing acerebellar (ace) mutants. fgf3 function was disrupted by injecting embryos with antisense morpholino oligomers (MO) specifically designed to block translation of fgf3 transcripts. Disruption of either fgf3 or fgf8 causes moderate reduction in the size of the otic vesicle. Injection of fgf3-MO into ace/ace mutants causes much more severe reduction or complete loss of otic tissue. Moreover, preplacode cells fail to express pax8 and pax2.1, indicating disruption of early stages of otic induction in fgf3-depleted ace/ace mutants. Both fgf3 and fgf8 are normally expressed in the germring by 50% epiboly and are induced in the primordium of rhombomere 4 by 80% epibloy. In addition, fgf3 is expressed during the latter half of gastrulation in the prechordal plate and paraxial cephalic mesendoderm, tissues that either pass beneath or persist near the prospective otic ectoderm. Conditions that alter the pattern of expression of fgf3 and/or fgf8 cause corresponding changes in otic induction. Loss of maternal and zygotic one-eyed pinhead (oep) does not alter expression of fgf3 or fgf8 in the hindbrain, but ablates mesendodermal sources of fgf signaling and delays otic induction by several hours. Conversely, treatment of wild-type embryos with retinoic acid greatly expands the periotic domains of expression of fgf3, fgf8, and pax8 and leads to formation of supernumerary and ectopic otic vesicles. These data support the hypothesis that fgf3 and fgf8 cooperate during the latter half of gastrulation to induce differentiation of otic placodes.

Animals↗

PubMed2003

Nil per os encodes a conserved RNA recognition motif protein required for morphogenesis and cytodifferentiation of digestive organs in zebrafish.

Digestive organ development occurs through a sequence of morphologically distinct stages, from overtly featureless endoderm, through organ primordia to, ultimately, adult form. The developmental controls that govern progression from one stage to the next are not well understood. To identify genes required for the formation of vertebrate digestive organs we performed a genetic screen in zebrafish. We isolated the nil per os (npo) mutation, which arrests morphogenesis and cytodifferentiation of the gut and exocrine pancreas in a primordial state. We identified the npo gene by positional cloning. It encodes a conserved protein, with multiple RNA recognition motifs, that is related to the yeast protein Mrd1p. During development npo is expressed in a dynamic fashion, functioning cell autonomously to promote organ cytodifferentiation. Antisense-mediated knockdown of npo results in organ hypoplasia, and overexpression of npo causes an overgrowth of gastrointestinal organs. Thus, npo is a gene essential for a key step in the gut morphogenetic sequence.

Amino Acid Motifs↗

PubMed2000

Zebrafish developmental genetics and central nervous system development.

The central nervous system (CNS) is the most complex tissue of vertebrates. Recently, the zebrafish has emerged as a powerful genetic system for studying early development, and large-scale mutagenic screens for embryonic patterning defects have been accomplished. Mutants isolated in these screens are proving helpful in unravelling the molecular hierarchies involved in the development of the CNS. We review here recent studies in zebrafish which shed light on the genetic pathways involved in induction and regionalization of the CNS.

Animals↗

PubMed2005

Cell proliferation in the developing lateral line system of zebrafish embryos.

The sensory organs of the embryonic lateral line system are deposited by migrating primordia that originate in the otic region. Here, we examine the pattern of cell proliferation in the posterior lateral line system. We conclude that three phases of cell proliferation are involved in the generation of this system, separated by two phases of mitotic quiescence. The first phase corresponds to generalized proliferation during gastrulation, followed by a first period of quiescence that may be related to the determination of the lateral line precursor cells. A second phase of proliferation takes place in the placode and migrating primordium. This region is organized in annuli that correspond to the expression of proneural/neurogenic genes. A second period of quiescence follows, corresponding to deposition and differentiation of the sensory organs. The third period of proliferation corresponds to continued renewal of hair cells by division of support cells within each sensory organ.

Animals↗

PubMed1999

Region-specific cell clones in the developing spinal cord of the zebrafish.

To analyse the proliferative abilities of cells within particular regions of the zebrafish neural plate, injections of fluorescein-dextran were made into single cells at either medial or intermediary positions in the neural plate region of two-somite stage embryos. The resulting cell clones were analysed in 3. 5-day-old embryos. Clones with similar compositions were found among those derived from injections in both regions, and these were grouped into classes. 78 clones 29 obtained following injections in the medial region, and 22 of 59 cell clones derived from injections in the intermediary region, were classifiable into 9 and 10 different classes, respectively, each comprising a variable number of clones. Several identified cell types, as well as each of the clone classes themselves, were specific for the regions of the neural plate from which they derived, i.e. they were not represented among the clones derived from the other region. These results suggest that the composition of the lineages derived from particular cells is constant in different animals.

Animals↗

PubMed2006

Essential role for Csk upstream of Fyn and Yes in zebrafish gastrulation.

Morphogenetic cell movements during gastrulation shape the vertebrate embryo bodyplan. Non-canonical Wnt signaling has been established to regulate convergence and extension cell movements that mediate anterior-posterior axis elongation. In recent years, many other factors have been implicated in the process by modulation of non-canonical Wnt signaling or by different, unknown mechanisms. We have found that the Src family kinases, Fyn and Yes, are required for normal convergence and extension cell movements in zebrafish embryonic development and they signal in parallel to non-canonical Wnts, eventually converging on a common downstream factor, RhoA. Here, we report that Csk, a negative regulator of Src family kinases has a role in gastrulation cell movements as well. Csk knock down induced a phenotype that was similar to the defects observed after knock down of Fyn and Yes, in that gastrulation cell movements were impaired, without affecting cell fate. The Csk knock down phenotype was rescued by simultaneous partial knock down of Fyn and Yes. We conclude that Csk acts upstream of Fyn and Yes to control vertebrate gastrulation cell movements.

Journal Article↗