Biology subjects

Jiang, Z.

Publications and source records attributed to Jiang, Z..

At least 217 records · Page 12Linked to original sources

bioRxiv2020

Genome-wide circadian rhythm detection methods: systematic evaluations and practical guidelines

Circadian rhythms are oscillations of behavior, physiology, and metabolism in many organisms. Recent advancements in omics technology make it possible for genome-wide profiling of circadian rhythms. Here, we conducted a comprehensive analysis of seven existing algorithms commonly used for circadian rhythm detection. Using gold-standard circadian and non-circadian genes, we systematically evaluated the accuracy and reproducibility of the algorithms on empirical datasets generated from various omics platforms under different experimental designs. We also carried out extensive simulation studies to test each algorithms robustness to key variables, including sampling patterns, replicates, waveforms, signal-to-noise ratios, uneven samplings, and missing values. Furthermore, we examined the distributions of the nominal p-values under the null and raised issues with multiple testing corrections using traditional approaches. With our assessment, we provide method selection guidelines for circadian rhythm detection, which are applicable to different types of high-throughput omics data. Key pointsO_LIVarious methods have been developed for circadian rhythm detection on a genome-wide scale using omics technologies, yet there has not been a comprehensive summary and evaluation of all existing methods to date. C_LIO_LIUsing gold-standard circadian and non-circadian genes, we systematically evaluated the accuracy and reproducibility of seven existing algorithms for circadian rhythm detection on empirical datasets generated from various omics platforms. C_LIO_LIWe carried out extensive simulation studies to test each algorithms robustness to key variables, including sampling patterns, replicates, waveforms, signal-to-noise ratios, uneven samplings, and missing values. C_LIO_LIWe examined the distributions of the nominal p-values under the null and raised issues with multiple testing corrections using the Benjamini-Hochberg procedure due to gene-gene correlation and testing being overly conservative. C_LIO_LIWe provide method selection guidelines for circadian rhythm detection, which are applicable to different types of high-throughput omics data. C_LI

bioinformatics↗

bioRxiv2020

Interpretable machine learning framework reveals novel gut microbiome features in predicting type 2 diabetes

Gut microbiome targets for type 2 diabetes (T2D) prevention among human cohorts have been controversial. Using an interpretable machine learning-based analytic framework, we identified robust human gut microbiome features, with their optimal threshold, in predicting T2D. Based on the results, we constructed a microbiome risk score (MRS), which was consistently associated with T2D across 3 independent Chinese cohorts involving 9111 participants (926 T2D cases). The MRS could also predict future glucose increment, and was correlated with a variety of gut microbiota-derived blood metabolites. Faecal microbiota transplantation from humans to germ-free mice demonstrated a causal role of the identified combination of microbes in the T2D development. We further identified adiposity and dietary factors which could prospectively modulate the MRS, and found that body fat distribution may be the key factor modulating the gut microbiome-T2D relationship. Taken together, we proposed a new analytical framework for the investigation of microbiome-disease relationship. The identified microbiota may serve as potential drug targets for T2D in future.

microbiology↗

bioRxiv2020

A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

The global spread of SARS-CoV-2 requires an urgent need to find effective therapeutics for the treatment of COVID-19. We developed a data-driven drug repositioning framework, which applies both machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. The retrospective study using the past SARS-CoV and MERS-CoV data demonstrated that our machine learning based method can successfully predict effective drug candidates against a specific coronavirus. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 is able to suppress the CpG-induced IL-6 production in peripheral blood mononuclear cells, suggesting that it may also have anti-inflammatory effect that is highly relevant to the prevention immunopathology induced by SARS-CoV-2 infection. Further pharmacokinetic and toxicokinetic evaluation in rats and monkeys showed a high concentration of CVL218 in lung and observed no apparent signs of toxicity, indicating the appealing potential of this drug for the treatment of the pneumonia caused by SARS-CoV-2 infection. Moreover, molecular docking simulation suggested that CVL218 may bind to the N-terminal domain of nucleocapsid (N) protein of SARS-CoV-2, providing a possible model to explain its antiviral action. We also proposed several possible mechanisms to explain the antiviral activities of PARP1 inhibitors against SARS-CoV-2, based on the data present in this study and previous evidences reported in the literature. In summary, the PARP1 inhibitor CVL218 discovered by our data-driven drug repositioning framework can serve as a potential therapeutic agent for the treatment of COVID-19.

systems biology↗

bioRxiv2020

Brassinosteroids Suppress Ethylene Biosynthesis via Transcription Factor BZR1 in Pear and Apple Fruit

The plant hormone ethylene is important for the ripening of climacteric fruit, such as pear (Pyrus ussuriensis), and the brassinosteroid (BR) class of phytohormones affects ethylene biosynthesis during ripening, although via an unknown molecular mechanism. Here, we observed that exogenous BR treatment suppressed ethylene production during pear fruit ripening, and that the expression of the transcription factor PuBZR1 was enhanced by epibrassinolide (EBR) treatment during pear fruit ripening. PuBZR1 was shown to interact with PuACO1, which converts 1-aminocyclopropane-1-carboxylic acid (ACC) to ethylene, and suppress its activity. We also observed that BR-activated PuBZR1 bound to the promoters of PuACO1 and of PuACS1a, which encodes ACC synthase, and directly suppressed their transcription. Moreover, PuBZR1 suppressed the expression of transcription factor PuERF2 by binding its promoter, and PuERF2 bound to the promoters of PuACO1 and PuACS1a. We concluded that PuBZR1 indirectly suppresses the transcription of PuACO1 and PuACS1a through its regulation of PuERF2. Ethylene production and the expression profiles of the corresponding apple (Malus domestica) homologs showed similar changes following EBR treatment. Together, these results suggest that BR-activated BZR1 suppresses ACO1 activity and the expression of ACO1 and ACS1a, thereby reducing ethylene production during pear and apple fruit ripening. This likely represents a conserved mechanism by which exogenous BR suppresses ethylene biosynthesis during climacteric fruit ripening. One-sentence summaryBR-activated BZR1 suppresses ACO1 activity and expression of ACO1 and ACS1a, which encode two ethylene biosynthesis enzymes, thereby reducing ethylene production during pear and apple fruit ripening.

plant biology↗

bioRxiv2020

Acute Stress Desensitizes Hypothalamic CRH Neurons to Norepinephrine and Physiological Stress

Noradrenergic afferents to corticotropin releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN) provide a major excitatory drive to the hypothalamic-pituitary-adrenal (HPA) axis via 1 adrenoreceptor activation. The ascending noradrenergic afferents are recruited preferentially by physiological, rather than psychological, stress modalities. Glucocorticoids secreted in response to HPA activation feed back onto the hypothalamus to negatively regulate the HPA axis, providing a critical autoregulatory constraint that prevents glucocorticoid overexposure. Whether differential negative feedback mechanisms target stress modality-specific HPA activation is not known. Here, we reveal a desensitization of the 1 adrenoreceptor activation of the HPA axis following acute stress that is mediated by rapid glucocorticoid regulation of adrenoreceptor trafficking. Prior stress desensitized the HPA axis to subsequent physiological, but not psychological, stress. Our findings demonstrate rapid glucocorticoid suppression of adrenoreceptor signaling in CRH neurons that is specific to physiological stress activation, and reveal, therefore, a rapid, modality-selective glucocorticoid feedback mechanism.

neuroscience↗

bioRxiv2019

The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for human complex diseases

There is increasing interest about the interplay between host genetics and gut microbiome on human complex diseases, with prior evidence mainly derived from animal models. In addition, the shared and distinct microbiome features among human complex diseases remain largely unclear. We performed a microbiome genome-wide association study to identify host genetic variants associated with gut microbiome in a Chinese population with 1475 participants. We then conducted bi-directional Mendelian randomization analyses to examine the potential causal associations between gut microbiome and human complex diseases. We found that Saccharibacteria (also known as TM7 phylum) could potentially improve renal function by affecting renal function biomarkers (i.e., creatinine and estimated glomerular filtration rate). In contrast, atrial fibrillation, chronic kidney disease and prostate cancer, as predicted by the host genetics, had potential causal effect on gut microbiome. Further disease-microbiome feature analysis suggested that gut microbiome features revealed novel relationship among human complex diseases. These results suggest that different human complex diseases share common and distinct gut microbiome features, which may help re-shape our understanding about the disease etiology in humans.

microbiology↗

bioRxiv2019

Suppression of Docetaxel induced apoptosis in Survivin-depleted cells due to failure of sustained mitotic block

The antitumor effect of taxanes have been attributed to their ability to induce mitotic arrest through activation of the spindle assembly checkpoint. Cell death following prolonged mitotic arrest is mediated by the intrinsic apoptosis pathway. Accordingly, factors that influence the robustness of mitotic arrest or disrupt the apoptotic machinery might confer drug resistance. Survivin is an inhibitor of apoptosis protein. Its overexpression has been associated with resistance to multiple anticancer agents including taxanes, and its targeting led to drug sensitization. On the other hand, Survivin is a key regulator of mitosis, which is shown to be required for stable activation of the spindle assembly checkpoint. Since the sensitivity of taxanes depends on a functional spindle checkpoint, inhibition of Survivin may lead to drug resistance, which is the opposite effect of its anti-apoptotic function. Here we show that Survivin-depleted cells escape the mitotic block following Docetaxel treatment, thereby evading drug induced apoptosis. Moreover, Survivin depletion increases the level of mitotic catastrophe and cellular senescence induced by Docetaxel and enhanced its efficacy against clonogenic survival of tumor cells. Our finding suggests that inhibition of Survivin promotes non-apoptotic mechanisms following Docetaxel treatment rather than increases the sensitivity of apoptosis.

cancer biology↗

bioRxiv2019

Widespread dose-dependent effects of RNA expression and splicing on complex diseases and traits

The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2,519 out of 5,385) of the GWAS loci examined. Our results demonstrate the translational relevance of the GTEx resources and highlight the need to increase their resolution and breadth to further our understanding of the genotype-phenotype link.

genetics↗

bioRxiv2019

The Manganese Salt (MnJ) Functions as A Potent Universal Adjuvant

Aluminum adjuvants have been used for a century in various vaccines due to its ability to potentiate humoral immunity and safety records since 1920s. Manganese is an essential micronutrient required for diverse biological activities in cells. We previously found that Mn2+ is a strong type I-interferon stimulator activating the cGAS-STING pathway. Herein we report that a colloidal manganese salt (MnJ) is a potent adjuvant to induce both humoral and cellular immune responses, particularly CTL activation. When administrated intranasally, MnJ was also a strong mucosal adjuvant, inducing high levels of IgA antibodies. MnJ strongly promoted dendritic cell maturation and antigen-specific T cell activation. Interestingly, IL-1/-18 induction and release by Mn2+-activated ASC-mediated inflammasomes were not observed. MnJ showed great adjuvant effects to all tested antigens including inactivated viruses, recombinant proteins and peptides by either intramuscular or intranasal immunization. These findings may have implications in developing potent but safe Mn2+-containing vaccines.

immunology↗

bioRxiv2019

Universal and distinct features of intra-population heterogeneity between differentiated cells and pluripotent stem cells

Isogenic cells cultured together show heterogeneity in their proliferation rate. To determine the differences between fast and slow-proliferating cells, we developed a method to sort cells by proliferation rate, and performed RNA-seq on slow and fast proliferating subpopulations of pluripotent mouse embryonic stem cells (mESCs) and mouse fibroblasts. We found that slowly proliferating mESCs have a more naive pluripotent character. We identified an evolutionarily conserved proliferation-correlated transcriptomic signature that is common to all eukaryotes: fast cells have higher expression of genes for protein synthesis and protein degradation. This signature accurately predicted growth rate in yeast and cancer cells, and identified lineage-specific proliferation dynamics during development, using C. elegans scRNA-seq data. In contrast, sorting by mitochondria membrane potential revealed a highly cell-type specific mitochondria-state related transcriptome. mESCs with hyperpolarized mitochondria are fast proliferating, while the opposite is true for fibroblasts. The mitochondrial electron transport chain inhibitor antimycin affected slow and fast subpopulations differently. While a major transcriptional-signature associated with cell-to-cell heterogeneity in proliferation is conserved, the metabolic and energetic dependency of cell proliferation is cell-type specific. SynopsisBy performing RNA-seq on cells FACS sorted by their proliferation rate, this study identifies a gene expression signature capable of predicting proliferation rates in diverse eukaryotic cell types and species. This signature, applied to scRNAseq data from C.elegans, reveals lineage-specific differences in proliferation during development. In contrast to the universality of the proliferation signature, mitochondria and metabolism related genes show a high degree of cell-type specificity; mouse pluripotent stem cells (mESCs) and differentiated cells (fibroblasts) exhibit opposite relations between mitochondria state and proliferation. Furthermore, we identified a slow proliferating subpopulation of mESCs with higher expression of pluripotency genes. Finally, we show that fast and slow proliferating subpopulations are differentially sensitive to mitochondria inhibitory drugs in different cell types. HighlightsO_LIA FACS-based method to determine the transcriptomes of fast and slow proliferating subpopulations. C_LIO_LIA universal proliferation-correlated transcriptional signature indicates high protein synthesis and degradation in fast proliferating cells across cell types and species. C_LIO_LIApplied to scRNA-seq, the expression signature predicts correctly the global slowdown in proliferation during C. elegans development, with lineage-specific exceptions. C_LIO_LIMitochondria membrane potential predicts proliferation rate in a cell-type specific manner, with ETC complex III inhibitor having distinct effects on the proliferation of fibroblasts vs mESCs. C_LI

systems biology↗

bioRxiv2019

Theory of active chromatin remodeling

Nucleosome positioning controls the accessible regions of chromatin and plays essential roles in DNA-templated processes. ATP driven remodeling enzymes are known to be crucial for its establishment in vivo, but their non-equilibrium nature has hindered the development of a unified theoretical framework for nucleosome positioning. Using a perturbation theory, we show that the effect of these enzymes can be well approximated by effective equilibrium models with rescaled temperatures and interactions. Numerical simulations support the accuracy of the theory in predicting both kinetic and steady-state quantities, including the effective temperature and the radial distribution function, in biologically relevant regimes. The energy landscape view emerging from our study provides an intuitive understanding for the impact of remodeling enzymes in either reinforcing or overwriting intrinsic signals for nucleosome positioning, and may help improve the accuracy of computational models for its prediction in silico.

biophysics↗

bioRxiv2019

3D observation of large-scale subcellular dynamics in vivo at the millisecond scale

Observing large-scale three-dimensional (3D) subcellular dynamics in vivo at high spatiotemporal resolution has long been a pursuit for biology. However, both the signal-to-noise ratio and resolution degradation in multicellular organisms pose great challenges. Here, we propose a method, termed Digital Adaptive Optics Scanning Lightfield Mutual Iterative Tomography (DAOSLIMIT), featuring both 3D incoherent synthetic aperture and tiled wavefront correction in post-processing. We achieve aberration-free fluorescence imaging in vivo over a 150 x 150 x 16 m3 field-of-view with the spatiotemporal resolution up to 250 nm laterally and 320 nm axially at 100 Hz, corresponding to a huge data throughput of over 15 Giga-voxels per second. Various fast subcellular processes are observed, including mitochondrial dynamics in cultured neurons, membrane dynamics in zebrafish embryos, and calcium propagation in cardiac cells, human cerebral organoids, and Drosophila larval neurons, enabling simultaneous in vivo studies of morphological and functional dynamics in 3D.

cell biology↗

bioRxiv2019

Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors

Drug resistance is a significant hindrance to effective cancer treatment. Although resistance mechanisms of epidermal growth factor receptor (EGFR)-mutant cancer cells to lethal EGFR tyrosine kinase inhibitors (TKI) treatment have been investigated intensively, how cancer cells orchestrate adaptive response under sublethal drug challenge remains largely unknown. Here we find that 2-hour sublethal TKI treatment elicits a transient drug-tolerant state in EGFR-mutant lung cancer cells. Continuous sublethal treatment reinforces this tolerance and eventually establishes long-term TKI resistance. This adaptive process involves H3K9 demethylation-mediated epigenetic upregulation of branched-chain amino acid aminotransferase 1 (BCAT1) and subsequent metabolic reprogramming, which promotes TKI resistance through attenuating reactive oxygen species (ROS) accumulation. Combinational treatment with TKI and ROS-inducing reagents overcomes this drug resistance in preclinical mouse models. Clinical information analyses support the correlation of BCAT1 expression with EGFR TKI response. Collectively, our findings reveal the importance of epigenetically regulated BCAT1-engaged metabolism reprogramming in TKI resistance in lung cancer.\n\nHIGHLIGHTSSublethal EGFR TKI treatment induces transient drug-tolerant state and long-term resistance in EGFR-mutant lung cancer cells\n\nEpigenetically regulated BCAT1-mediated metabolic reprogramming orchestrates EGFR TKI-induced drug resistance\n\nCombinational treatment with TKI and ROS-inducing agents overcomes the drug resistance induced by EGFR TKI treatment

cancer biology↗

bioRxiv2019

The rs6505162 C>A polymorphism in the miRNA-423 gene exhibits a protective element of coronary artery in a southern Chinese population with Kawasaki disease

BackgroundManifesting as acute rash, fever and vasculitis, belonging to autoimmune syndrome, Kawasaki disease(KD) is prone to occur in infants and young children. Males and females is affected by KD at a ratio of 1.4 to 1.7: 1. KD is known to own many common clinical manifestations and complications, like coronary artery lesion(CAL) and coronary artery aneurysm(CAA). Polymorphisms of the rs6505162 locus in the miRNA-423 gene are associated with enhancive susceptibility to coronary artery disease and the alterations of the four cytokines IL-4., IL-10, IL-21, IL-22 in the early stages of diabetes. However, no researcher has reported whether rs6505162 is related to KD susceptibility or no. Therefore, we carried out the trial concentrating on the connection between miRNA-423 rs6505162 C>A polymorphism and KD susceptibility.\n\nMethodsTo obtain the genotypes of rs6505162 in objects enrolled by 532 KD children and 623 control, we applied Taqman real-time PCR and all statistical analyses was carried out by SAS.\n\nResultsThe comparison between all cases and all controls hinted that the rs6505162C>A polymorphism has no relationship with KD susceptibility. Nevertheless, a subgroup analysis revealed that the CA/AA genotypes of rs6505162 could reduce the occurrence of CAA (Adjusted age and gender odds ratio=1.30, 95%CI=1.02-1.67, P=0.037) and CAL (Adjusted OR=1.56, 95%CI=1.19-2.03, P=0.001)in KD patients.\n\nConclusionOur final results stated clearly that miRNA-423 rs6505162 polymorphism appears to be a protective element of CAL and CAA in southern Chinese suffers with KD.

genetics↗

bioRxiv2019

Sodium nitroprusside prevents the detrimental effects of glucose on the neurovascular unit and behaviour in zebrafish

Diabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood, and currently no treatment exists to prevent these negative effects. We previously found that the NO donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish and the ability of SNP to prevent these.\n\nWe incubated 4 days post fertilisation (dpf) zebrafish embryos in 20mM glucose or mannitol for five days until 9dpf, with or without 0.1mM SNP co-treatment for 24h (8-9dpf), and quantified vascular nitric oxide reactivity, vascular mural cell number, expression of a klf2a reporter, glial fibrillary acidic protein (GFAP) and TRPV4, as well as spontaneous neuronal activation at 9dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies.\n\nWe find that glucose exposure significantly reduced nitric oxide reactivity, klf2a reporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour we found glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure.\n\nOur findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype, and function of the optic tectum and on whole organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit.

neuroscience↗

bioRxiv2019

Quantitative investigation of factors relevant to the T cell spot test for tuberculosis infection in active tuberculosis

BackgroundPrevious qualitative studies suggested that the false negative rate of T cell spot test for tuberculosis infection (T-SPOT.TB) is associated with many risk factors in tuberculosis patients; However, more precise quantitative studies are not well known. ObjectiveTo investigate the factors affecting quantified T-SPOT.TB in patients with active tuberculosis. MethodsWe retrospectively analyzed the data of 360 patients who met the inclusion criteria. Using the levels of early secreted antigenic target 6 kDa (ESAT-6) and culture filtrate protein 10 kDa (CFP-10) as dependent variables, variables with statistical significance in the univariate analysis were subjected to optimal scaling regression analysis. ResultsThe results showed that the ESAT-6 regression model had statistical significance (P-trend < 0.001) and that previously treated cases, CD4+ and platelet count were its independent risk factors (all P-trend < 0.05); their importance levels were 0.095, 0.596 and 0.100, respectively, with a total of 0.791. The CFP-10 regression model also had statistical significance (P-trend < 0.001); platelet distribution width and alpha-2 globulin were its independent risk factors (all P-trend < 0.05), their importance levels were 0.287 and 0.247, respectively, with a total of 0.534. The quantification graph showed that quantified T-SPOT.TB levels had a linear correlation with risk factors. ConclusionThe test results of T-SPOT.TB should be given more precise explanations, especially in patients with low levels of CD4+, platelet, alpha-2 globulin and high platelet distribution width.

epidemiology↗

bioRxiv2019

Direct synthesis of EM-visible gold nanoparticles on genetically encoded tags for single-molecule visualization in cells

Single-molecule visualization in cells with genetically encoded tags for electron microscopy (EM) has been a long-awaited but unimplemented tool for cell biologists. Here, we report an approach for directly synthesizing EM-visible gold nanoparticles (AuNPs) on cysteine-rich tags for single-molecule visualization in cells. We first uncovered an auto-nucleation suppression mechanism that allows specific synthesis of AuNPs on isolated cysteine-rich tags. We next exploited this mechanism to develop an approach for single-molecule detection of proteins in prokaryotic cells and achieved an unprecedented labeling efficiency. We then expanded it to more complicated eukaryotic cells and successfully detected the proteins targeted to various organelles, including the membranes of endoplasmic reticulum (ER) and nuclear envelope, ER lumen, nuclear pores, spindle pole bodies, and mitochondrial matrix. Thus, our implementation of genetically encoded tags for EM should allow cell biologists to address an enormous range of biological questions at single-molecule level in diverse cellular ultrastructural contexts without using antibodies.

biophysics↗

bioRxiv2018

foxc1a and foxc1b differentially regulate angiogenesis from arteries and veins by modulating Vascular Endothelial Growth Factor signalling

The forkhead transcription factors Foxc1 and Foxc2 are essential to establish intact vascular networks in mammals. How these genes interact with endothelial signalling pathways to exert their functions remains incompletely understood. We have generated novel zebrafish mutants in foxc1a and foxc1b, the zebrafish orthologues of mammalian Foxc1, to determine their function during angiogenesis. foxc1a mutants display abnormal formation of cranial veins including the primordial hindbrain channels (PHBC), reduced Vascular Endothelial Growth Factor (VEGF) receptor expression in these and loss of central arteries. foxc1b mutants are normal, whereas foxc1a; foxc1b double mutants exhibit ectopic angiogenesis from trunk segmental arteries. Dll4/Notch signalling is reduced in foxc1a; foxc1b double mutant arteries and ectopic angiogenesis can be suppressed by induction of Notch or inhibition of Vegfc signalling. We conclude that foxc1a and foxc1b play compensatory and context-dependent roles to co-ordinate angiogenesis by promoting venous sprouting via induction of VEGF receptor expression whilst antagonising arterial sprouting by inducing Dll4/Notch signalling. foxc1a/b mediated induction of both pro- and anti-angiogenic axes of VEGF-Dll4/Notch negative feedback imparts competition to balance arterial and venous angiogenesis within developing vascular beds.\n\nSummary Statementfoxc1a and foxc1b promote angiogenesis from veins and suppress angiogenesis from arteries by promoting competing pro-angiogenic Vascular Endothelial Growth Factor signalling, and anti-angiogenic Dll4/Notch signalling in zebrafish embryos.

developmental biology↗