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Project description:Coronary heart disease (CHD) is a leading cause of death worldwide, and angiogenesis plays important roles in CHD. Thus, in the present study, the angiogenic efficacy of four common cardiovascular medicines (aspirin, pravastatin, metoprolol and isosorbide mononitrate (ISMN)) was determined by the number and length of zebrafish intersegmental vessels (ISVs) after immersing zebrafish embryos in different medicines. Results showed that ISMN significantly increased the length and number of ISVs. ISMN is a long-acting nitrate ester drug. It has been used as a vasodilator to dilate arteries and veins to reduce the cardiac preload and postload. However, the effect of ISMN on angiogenesis remains unclear. Thus, by in vitro experiments, the angiogenic mechanism of ISMN was evaluated through detecting the viability and proliferation of human umbilical vein endothelial cells (HUVECs) and the expression of angiogenesis-related genes and miRNAs. Results indicated that ISMN could increase the viability and proliferation of HUVECs by decreasing apoptosis, and elevated the expressions of vedf, kdrl, pdgfr in zebrafish embryos. Furthermore, the expressions of miR-126, miR-130a and miR-210 were also regulated in ISMN-treated HUVECs. In conclusion, ISMN could promote angiogenesis in zebrafish embryos and HUVECs, implying ISMN may be a potential therapeutic in treating angiogenesis-related diseases.
| S-EPMC7380327 | biostudies-literature
Project description:Growth hormone receptor (GHR), a member of the class I cytokine receptor family, plays key roles in cancer progression. Recently, GHR has been reported to be associated with breast cancer development, but the molecular mechanism of GHR in this malignancy is not fully understood. To investigate this issue, we stably inhibited GHR in breast cancer cell lines, which were observed to reduce cell proliferation, tumor growth and induction of apoptosis, and arrest the cell-cycle arrest at the G1-S phase transition. In addition, GHR silencing suppressed the protein levels of B-Raf proto-oncogene, serine/threonine kinase (BRAF), Mitogen-activated protein kinase kinase (MEK) and Extracellular regulated protein kinases (ERK). These findings suggest that GHR may mediate breast cell progression and apoptosis through control of the cell cycle via the BRAF/MEK/ERK signaling pathway.
| S-EPMC7262926 | biostudies-literature
Project description:Prostaglandin (PG)-E2 is essential for growth and development of vertebrates. PGE2 binds to G-coupled receptors to regulate embryonic stem cell differentiation and maintains tissue homeostasis. Overproduction of PGE2 by breast tumor cells promotes aggressive breast cancer phenotypes and tumor-associated lymphangiogenesis. In this study, we investigated novel roles of PGE2 in early embryonic vascular development and maturation with the microinjection of PGE2 in fertilized zebrafish (Danio rerio) eggs. We injected Texas Red dextran to trace vascular development. Embryos injected with the solvent of PGE2 served as vehicle. Distinct developmental changes were noted from 28-96 h post fertilization (hpf), showing an increase in embryonic tail flicks, pigmentation, growth, hatching and larval movement post-hatching in the PGE2-injected group compared to the vehicle. We recorded a significant increase in trunk vascular fluorescence and maturation of vascular anatomy, embryo heartbeat and blood vessel formation in the PGE2 injected group. At 96 hpf, all larvae were euthanized to measure vascular marker mRNA expression. We observed a significant increase in the expression of stem cell markers efnb2a, ephb4a, angiogenesis markers vegfa, kdrl, etv2 and lymphangiogenesis marker prox1 in the PGE2-group compared to the vehicle. This study shows the novel roles of PGE2 in promoting embryonic vascular maturation and angiogenesis in zebrafish.This article has an associated First Person interview with the first author of the paper.
| S-EPMC6504002 | biostudies-literature
Project description:Fibroblast growth factor (Fgf) signaling regulates many processes during development. In most cases, one tissue layer secretes an Fgf ligand that binds and activates an Fgf receptor (Fgfr) expressed by a neighboring tissue. Although studies have identified the roles of specific Fgf ligands during development, less is known about the requirements for the receptors. We have generated null mutations in each of the five fgfr genes in zebrafish. Considering the diverse requirements for Fgf signaling throughout development, and that null mutations in the mouse Fgfr1 and Fgfr2 genes are embryonic lethal, it was surprising that all zebrafish homozygous mutants are viable and fertile, with no discernable embryonic defect. Instead, we find that multiple receptors are involved in coordinating most Fgf-dependent developmental processes. For example, mutations in the ligand fgf8a cause loss of the midbrain-hindbrain boundary, whereas, in the fgfr mutants, this phenotype is seen only in embryos that are triple mutant for fgfr1a;fgfr1b;fgfr2, but not in any single or double mutant combinations. We show that this apparent fgfr redundancy is also seen during the development of several other tissues, including posterior mesoderm, pectoral fins, viscerocranium, and neurocranium. These data are an essential step toward defining the specific Fgfrs that function with particular Fgf ligands to regulate important developmental processes in zebrafish.
| S-EPMC6707458 | biostudies-literature
Project description:Chicken and zebrafish are two model species regularly used to study the role of thyroid hormones in vertebrate development. Similar to mammals, chickens have one thyroid hormone receptor ? (TR?) and one TR? gene, giving rise to three TR isoforms: TR?, TR?2, and TR?0, the latter with a very short amino-terminal domain. Zebrafish also have one TR? gene, providing two TR?1 variants. The zebrafish TR? gene has been duplicated, and at least three TR? isoforms are expressed: TR?A1-2 and TR?B are very similar, while TR?A1 has a longer carboxy-terminal ligand-binding domain. All these TR isoforms appear to be functional, ligand-binding receptors. As in other vertebrates, the different chicken and zebrafish TR isoforms have a divergent spatiotemporal expression pattern, suggesting that they also have distinct functions. Several isoforms are expressed from the very first stages of embryonic development and early chicken and zebrafish embryos respond to thyroid hormone treatment with changes in gene expression. Future studies in knockdown and mutant animals should allow us to link the different TR isoforms to specific processes in embryonic development.
| S-EPMC3134294 | biostudies-literature
Project description:Treatment of fetal rat and embryonic chicken with exogenous glucocorticoids induces premature differentiation of growth hormone (GH) secreting cells. The effect of corticosterone (CORT) on somatotroph differentiation was mostly studied in pituitary cells in vitro. Currently, there is no evidence for glucocorticoid-mediated induction of somatotroph differentiation during pituitary development in bird species other than chicken. In this study, we sought to find out if in ovo injection of corticosterone into developing goose embryos could induce premature increase of GH in somatotrophs. On embryonic day (e) 15, the albumen of fertile goose eggs was injected with 300 ?l of 0.9% saline, 300 ?l 5 × 10-8M CORT, or 300 ?l 5 × 10-6 M CORT. Embryos were allowed to develop until e20 and e28 and isolated pituitaries were subjected to quantitative real-time PCR and immunocytochemistry to detect GH mRNA and protein, respectively. At e20 and e28, blood from chorioallantoic vessels was subjected to radioimmunoassay for analysis of plasma GH protein. In ovo administration of exogenous corticosterone brought about a 2.5-fold increase in the expression of GH mRNA and increased the in situ expression of GH protein in goose pituitary cells, and enhanced plasma GH levels compared to that of the respective controls at e20. These findings prove that administration of glucocorticoid could stimulate the expression of GH in somatotrophs during goose embryonic development. Our results suggest the probable involvement of membrane glucocorticoid receptor in the corticosterone mediated expression of GH. Together with previously published data, our results suggest that corticosterone mediated induction of GH expression during embryonic development is relatively conserved among different vertebrates.
| S-EPMC6105744 | biostudies-literature
Project description:The role of thyroid hormones (THs) in development has been extensively studied, however, the specific molecular mechanisms involved are far from being clear. THs act by binding to TH nuclear receptors (TR) that act as ligand-dependent transcription factors to regulate TH-dependent gene expression. Like vertebrates, zebrafish express different isoforms of functional Tr alpha and beta, some of which can bind alternative ligands like 3,5-T2. In this study, we first analyzed the effects of exogenous T3 and 3,5-T2 exposure during embryogenesis. The percentage of affected embryos was similar to those vehicle-injected, suggesting that the early exposure to low TH levels is not sufficient to elicit effects upon the phenotype of the embryo. We then generated crispants for four isoforms of thr to learn more about the role of these receptors in early development. We found that crispant larvae from thraa and a newly identified l-thrb+, but not thrab and canonical thrb1 showed profound deleterious effects upon symmetry and laterality, suggesting early novel roles for these Tr isoforms in the body plan developmental program. Since critical events that determine cell fate start in the late gastrula, we tested if some genes that are expressed during early developmental stages could indeed be TH targets. We identify early development genes, like sox10 and eve, that were specifically over-expressed in thraa and l-thrb+ crispants, suggesting that these specific thr isoforms function as transcription repressors for these genes, while transcription of zic and ets appear to be thraa and l-thrb+-mediated, respectively. Overall, present results show that TH signaling participates in early zebrafish development and identify Tr isoform-specific mediated regulation of early gene expression.
| S-EPMC6427925 | biostudies-literature
Project description:MVP17 encodes a mitochondrial inner-membrane protein, and mutation of human MVP17 can cause mitochondria DNA depletion syndrome (MDDS). However, the underlying function of mpv17 is still elusive. Here, we developed a new mutant with mpv17 knockout by using the CRISPR/Cas9 system. The mpv17-/- zebrafish showed developmental defects in muscles, liver, and energy supply. The mpv17-/- larvae hardly survived beyond a month, and they showed abnormal growth during the development stage. Abnormal swimming ability was also found in the mpv17-/- zebrafish. The transmission electron microscope (TEM) observation indicated that the mpv17-/- zebrafish underwent severe mitochondria dysfunction and the disorder of mitochondrial cristae. As an energy producer, the defects of mitochondria significantly reduced ATP content in mpv17-/- zebrafish, compared to wild-type zebrafish. We hypothesized that the disorder of mitochondria cristae was contributed to the dysfunction of muscle and liver in the mpv17-/- zebrafish. Moreover, the content of major energy depot triglycerides (TAG) was decreased dramatically. Interestingly, after rescued with normal exogenous mitochondria by microinjection, the genes involved in the TAG metabolism pathway were recovered to a normal level. Taken together, this is the first report of developmental defects in muscles, liver, and energy supply via mitochondria dysfunction, and reveals the functional mechanism of mpv17 in zebrafish.
| S-EPMC8449779 | biostudies-literature
Project description:Human embryonic stem cells (hESCs) provide an important means to effectively study soluble and cell-bound mediators that regulate development of early blood and endothelial cells in a human model system. Here, several complementary methods are used to demonstrate canonical Wnt signaling is important for development of hESC-derived cells with both hematopoietic and endothelial potential. Analyses using both standard flow cy-tometry, as well the more detailed high-throughput image scanning flow cytometry, characterizes sequential development of distinct early developing CD34(bright)CD31(+)Flk1(+) cells and a later population of CD34(dim)CD45(+) cells. While the CD34(bright)CD31(+)Flk1(+) have a more complex morphology and can develop into both endothelial cells and hematopoietic cells, the CD34(dim)CD45(+) cells have a simpler morphology and give rise to only hematopoietic cells. Treatment with dickkopf1 to inhibit Wnt signaling results in a dramatic decrease in development of cells with hematoendothelial potential. In addition, activation of the canonical Wnt signaling pathway in hESCs by coculture with stromal cells that express Wnt1, but not use of noncanonical Wnt5-expressing stromal cells, results in an accelerated differentiation and higher percentage of CD34(bright)CD31(+)Flk1(+) cells at earlier stages of differentiation. These studies effectively demonstrate the importance of canonical Wnt signaling to mediate development of early hematoendothelial progenitors during human development.
| S-EPMC2200802 | biostudies-other
Project description:Wnt/β-catenin signaling contributes to patterning, proliferation, and differentiation throughout vertebrate neural development. Wnt/β-catenin signaling is important for mammalian midbrain dopaminergic neurogenesis, while little is known about its role in ventral forebrain dopaminergic development. Here, we focus on the A11-like, Otp-dependent diencephalospinal dopaminergic system in zebrafish. We show that Wnt ligands, receptors and extracellular antagonist genes are expressed in the vicinity of developing Otp-dependent dopaminergic neurons. Using transgenic Wnt/β-catenin-reporters, we found that Wnt/β-catenin signaling activity is absent from these dopaminergic neurons, but detected Wnt/β-catenin activity in cells adjacent to the caudal DC5/6 clusters of Otp-dependent dopaminergic neurons. Pharmacological manipulations of Wnt/β-catenin signaling activity, as well as heat-shock driven overexpression of Wnt agonists and antagonists, interfere with the development of DC5/6 dopaminergic neurons, such that Wnt/β-catenin activity positively correlates with their number. Wnt/β-catenin activity promoted dopaminergic development specifically at stages when DC5/6 dopaminergic progenitors are in a proliferative state. Our data suggest that Wnt/β-catenin signaling acts in a spatially and temporally restricted manner on proliferative dopaminergic progenitors in the hypothalamus to positively regulate the size of the dopaminergic neuron groups DC5 and DC6.
| S-EPMC8770493 | biostudies-literature