Genomes and Genes
Gene Symbol: dll4
Description: delta-like 4 (Drosophila)
Alias: si:ch211-244p18.5, zgc:136596, delta-like protein 4
- Wythe J, Dang L, Devine W, Boudreau E, Artap S, He D, et al. ETS factors regulate Vegf-dependent arterial specification. Dev Cell. 2013;26:45-58 pubmed publisher..signaling specifies arterial fate during early vascular development by inducing the transcription of Delta-like 4 (Dll4), the earliest Notch ligand gene expressed in arterial precursor cells...
- Siekmann A, Lawson N. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature. 2007;445:781-4 pubmed..Finally, loss of the Notch ligand dll4 (delta-like 4) also leads to an increased number of endothelial cells within segmental arteries...
- Geudens I, Herpers R, Hermans K, Segura I, Ruiz de Almodovar C, Bussmann J, et al. Role of delta-like-4/Notch in the formation and wiring of the lymphatic network in zebrafish. Arterioscler Thromb Vasc Biol. 2010;30:1695-702 pubmed publisher..Knockdown of delta-like-4 (Dll4) or its receptors Notch-1b or Notch-6 in zebrafish impaired lymphangiogenesis...
- Covassin L, Siekmann A, Kacergis M, Laver E, Moore J, Villefranc J, et al. A genetic screen for vascular mutants in zebrafish reveals dynamic roles for Vegf/Plcg1 signaling during artery development. Dev Biol. 2009;329:212-26 pubmed publisher..Together our genetic analyses suggest that Vegf/Plcg1 signaling acts at multiple time points and in different signaling contexts to mediate distinct aspects of artery development. ..
- Wang L, Zhang P, Wei Y, Gao Y, Patient R, Liu F. A blood flow-dependent klf2a-NO signaling cascade is required for stabilization of hematopoietic stem cell programming in zebrafish embryos. Blood. 2011;118:4102-10 pubmed publisher..Taken together, we have demonstrated that blood flow is essential for HSC development and is mediated by a klf2a-NO signaling cascade in zebrafish. ..
- Hasan S, Tsaryk R, Lange M, Wisniewski L, Moore J, Lawson N, et al. Endothelial Notch signalling limits angiogenesis via control of artery formation. Nat Cell Biol. 2017;19:928-940 pubmed publisherAngiogenic sprouting needs to be tightly controlled. It has been suggested that the Notch ligand dll4 expressed in leading tip cells restricts angiogenesis by activating Notch signalling in trailing stalk cells...
- Lee J, Fei P, Packard R, Kang H, Xu H, Baek K, et al. 4-Dimensional light-sheet microscopy to elucidate shear stress modulation of cardiac trabeculation. J Clin Invest. 2016;126:1679-90 pubmed publisher..Subjecting endothelial cells to pulsatile flow in the presence of the ADAM10 inhibitor corroborated shear stress-activated Notch signaling to modulate trabeculation. ..
- Henke K, Daane J, Hawkins M, Dooley C, Busch Nentwich E, Stemple D, et al. Genetic Screen for Postembryonic Development in the Zebrafish (Danio rerio): Dominant Mutations Affecting Adult Form. Genetics. 2017;207:609-623 pubmed publisher..Taken together, these results show that dominant screens are a feasible and productive means to identify mutations that can further our understanding of gene function during postembryonic development and in disease. ..
- Quillien A, Moore J, Shin M, Siekmann A, Smith T, Pan L, et al. Distinct Notch signaling outputs pattern the developing arterial system. Development. 2014;141:1544-52 pubmed publisher..Together, these findings demonstrate that Notch acts in distinct contexts to initiate and maintain artery identity during embryogenesis. ..
- Liu L, Lin M, Lai Z, Jiang J, Huang Y, Jao L, et al. Motor neuron-derived Thsd7a is essential for zebrafish vascular development via the Notch-dll4 signaling pathway. J Biomed Sci. 2016;23:59 pubmed publisher..found that Thsd7a morphants displayed distinct phenotypes that are very similar to the loss of Notch-delta like 4 (dll4) signaling...
- Jiang Q, Lagos Quintana M, Liu D, Shi Y, Helker C, Herzog W, et al. miR-30a regulates endothelial tip cell formation and arteriolar branching. Hypertension. 2013;62:592-8 pubmed publisher..We investigated the contribution of miR-30 family members in arteriolar branching morphogenesis via delta-like 4 (Dll4)-Notch signaling in a zebrafish model. The miR-30 family consists of 5 members (miR-30a-e)...
- Chiang I, Fritzsche M, Pichol Thievend C, Neal A, Holmes K, Lagendijk A, et al. SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development. Development. 2017;144:2629-2639 pubmed publisher..These findings position SoxF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates. ..
- Feng N, Chen H, Fu S, Bian Z, Lin X, Yang L, et al. HIF-1Î± and HIF-2Î± induced angiogenesis in gastrointestinal vascular malformation and reversed by thalidomide. Sci Rep. 2016;6:27280 pubmed publisher..growth factor (VEGF) was a direct target of HIF-2Î± and that HIF-1Î± and HIF-2Î± regulated NOTCH1, Ang2, and DLL4, which enhanced vessel-forming of endothelial cells...
- Fish J, Cantu Gutierrez M, Dang L, Khyzha N, Chen Z, Veitch S, et al. Dynamic regulation of VEGF-inducible genes by an ERK/ERG/p300 transcriptional network. Development. 2017;144:2428-2444 pubmed publisher..By assessing the signals responsible for induction of the Notch ligand delta-like 4 (DLL4) in endothelial cells, we find that activation of the MAPK/ERK pathway mirrors the rapid and dynamic induction of <..
- Hermkens D, van Impel A, Urasaki A, Bussmann J, Duckers H, Schulte Merker S. Sox7 controls arterial specification in conjunction with hey2 and efnb2 function. Development. 2015;142:1695-704 pubmed publisher..Hence, sox7 levels are crucial in arterial specification in conjunction with hey2 and efnb2 function, with mutants in all three genes displaying shunt formation and an arterial block. ..
- Rowlinson J, Gering M. Hey2 acts upstream of Notch in hematopoietic stem cell specification in zebrafish embryos. Blood. 2010;116:2046-56 pubmed publisher..These results establish an essential role for Hey2 upstream of Notch in HSC formation. ..
- Samsa L, Givens C, Tzima E, Stainier D, Qian L, Liu J. Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish. Development. 2015;142:4080-91 pubmed publisher..Together, our findings describe an essential role for cardiac contraction-responsive transcriptional changes in endocardial cells to regulate cardiac chamber maturation. ..
- Packard R, Baek K, Beebe T, Jen N, Ding Y, Shi F, et al. Automated Segmentation of Light-Sheet Fluorescent Imaging to Characterize Experimental Doxorubicin-Induced Cardiac Injury and Repair. Sci Rep. 2017;7:8603 pubmed publisher..05, n?=?6-14). Our approach provides a high-throughput model with translational implications for drug discovery and genetic modifiers of chemotherapy-induced cardiomyopathy. ..
- Lu X, Wei Y, Liu F. Direct regulation of p53 by miR-142a-3p mediates the survival of hematopoietic stem and progenitor cells in zebrafish. Cell Discov. 2015;1:15027 pubmed publisher..Therefore, our work reveals the significance of the miR-142a-3p-p53 pathway in controlling hematopoietic stem and progenitor cell survival, and thus advances our understanding of the role of p53 in vertebrate hematopoiesis. ..
- Novodvorsky P, Watson O, Gray C, Wilkinson R, Reeve S, Smythe C, et al. klf2ash317 Mutant Zebrafish Do Not Recapitulate Morpholino-Induced Vascular and Haematopoietic Phenotypes. PLoS ONE. 2015;10:e0141611 pubmed publisher..The klf2ash317 mutation produces a truncated Klf2a protein but, unlike morpholino induced klf2a knockdown, does not affect cardiovascular development. ..
- Wang X, Yu Q, Wu Q, Bu Y, Chang N, Yan S, et al. Genetic interaction between pku300 and fbn2b controls endocardial cell proliferation and valve development in zebrafish. J Cell Sci. 2013;126:1381-91 pubmed publisher..We conclude that pku300 and fbn2b represent the few genes capable of regulating endocardial cell proliferation and signaling in zebrafish cardiac valve development. ..
- Biyashev D, Veliceasa D, Topczewski J, Topczewska J, Mizgirev I, Vinokour E, et al. miR-27b controls venous specification and tip cell fate. Blood. 2012;119:2679-87 pubmed publisher..We have identified its targets, a Notch ligand Delta-like ligand 4 (Dll4) and Sprouty homologue 2 (Spry2)...
- Eom D, Bain E, Patterson L, Grout M, Parichy D. Long-distance communication by specialized cellular projections during pigment pattern development and evolution. elife. 2015;4: pubmed publisher..Our study reveals a novel mechanism of cellular communication, roles for differentiation state heterogeneity in pigment cell interactions, and an unanticipated morphogenetic behavior contributing to a striking difference in adult form. ..
- Hogan B, Bussmann J, Wolburg H, Schulte Merker S. ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish. Hum Mol Genet. 2008;17:2424-32 pubmed publisher..Finally, we show that ccm1 function is cell autonomous, suggesting that it is endothelial cellular morphogenesis that is regulated by CCM proteins during development and pathogenesis. ..
- Wei Y, Ma D, Gao Y, Zhang C, Wang L, Liu F. Ncor2 is required for hematopoietic stem cell emergence by inhibiting Fos signaling in zebrafish. Blood. 2014;124:1578-85 pubmed publisher..Thus, our findings identify a novel regulatory mechanism for Ncor2 through Fos-Vegfd-Notch signaling cascade during HSC development in zebrafish embryos. ..
- Shi Y, Yuan W, Wang X, Gong J, Zhu S, Chai L, et al. Combretastatin A-4 efficiently inhibits angiogenesis and induces neuronal apoptosis in zebrafish. Sci Rep. 2016;6:30189 pubmed publisher..In addition, notch1a was up-regulated in CA-4 treated embryos, and inhibition of Notch signaling by DAPT partially rescued the apoptosis in zebrafish central nervous system caused by CA-4. ..
- Izumi N, Helker C, Ehling M, Behrens A, Herzog W, Adams R. Fbxw7 controls angiogenesis by regulating endothelial Notch activity. PLoS ONE. 2012;7:e41116 pubmed publisher..Growth of retinal blood vessel was impaired and the Notch ligand Dll4, which is also a Notch target, upregulated in inducible and endothelial cell-specific Fbxw7(iECKO) mutant mice...
- Dias T, Yang Y, Ogai K, Becker T, Becker C. Notch signaling controls generation of motor neurons in the lesioned spinal cord of adult zebrafish. J Neurosci. 2012;32:3245-52 pubmed publisher..This demonstrates that Notch is a negative signal for regenerative neurogenesis, and, importantly, that spinal motor neuron regeneration can be augmented in an adult vertebrate by inhibiting Notch signaling. ..
- Kimura Y, Satou C, Higashijima S. V2a and V2b neurons are generated by the final divisions of pair-producing progenitors in the zebrafish spinal cord. Development. 2008;135:3001-5 pubmed publisher..We report that the terminal division of pair-producing progenitor cells in vertebrate neurogenesis can reproducibly produce two distinct neurons through a mechanism that may not depend on the orientation of the division axis. ..
- Palardy G, Chitnis A. Identification of the Mind Bomb1 Interaction Domain in Zebrafish DeltaD. PLoS ONE. 2015;10:e0127864 pubmed publisher..As a result, ectopic expression of DeltaD lacking an effective MID results in a failure of Notch-mediated lateral inhibition and a neurogenic phenotype. ..
- Dunworth W, Cardona Costa J, Bozkulak E, Kim J, Meadows S, Fischer J, et al. Bone morphogenetic protein 2 signaling negatively modulates lymphatic development in vertebrate embryos. Circ Res. 2014;114:56-66 pubmed publisher..Our data identify BMP2 as a key negative regulator for the emergence of the lymphatic lineage during vertebrate development. ..
- Quillien A, Abdalla M, Yu J, Ou J, Zhu L, Lawson N. Robust Identification of Developmentally Active Endothelial Enhancers in Zebrafish Using FANS-Assisted ATAC-Seq. Cell Rep. 2017;20:709-720 pubmed publisher..Thus, FANS-assisted ATAC-seq using transgenic zebrafish embryos provides a robust approach for genome-wide identification of active tissue-specific enhancer elements. ..
- Ulrich F, Carretero Ortega J, MenÃ©ndez J, Narvaez C, Sun B, Lancaster E, et al. Reck enables cerebrovascular development by promoting canonical Wnt signaling. Development. 2016;143:147-59 pubmed publisher..Together, our findings have broad implications for both vascular and cancer biology. ..
- Tu X, Deng Y, Chen J, Hu Q, He C, Jordan J, et al. Screening study on the anti-angiogenic effects of Traditional Chinese Medicine - Part I: Heat-clearing and detoxicating TCM. J Ethnopharmacol. 2016;194:280-287 pubmed publisher..The results provide new insights into their clinical application and therapeutic potential for the management of angiogenesis-dependent diseases such as cancer. ..
- Vanhollebeke B, Stone O, Bostaille N, Cho C, Zhou Y, Maquet E, et al. Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/Î²-catenin pathway during brain angiogenesis. elife. 2015;4: pubmed publisher..Our results identify molecular determinants of ligand specificity of Wnt/Î²-catenin signaling and provide evidence for organ-specific control of vascular invasion through tight modulation of tip cell function. ..
- Jung H, Castranova D, Swift M, Pham V, Venero Galanternik M, Isogai S, et al. Development of the larval lymphatic system in zebrafish. Development. 2017;144:2070-2081 pubmed publisher..Our results show that major trunk lymphatic vessels are conserved in the zebrafish, and provide a thorough and complete description of trunk lymphatic vessel assembly. ..
- Zhen F, Lan Y, Yan B, Zhang W, Wen Z. Hemogenic endothelium specification and hematopoietic stem cell maintenance employ distinct Scl isoforms. Development. 2013;140:3977-85 pubmed publisher..Thus, our data suggest that a defined hemogenic endothelial population preset by scl-? supports the deterministic emergence of HSCs, and unravel the cellular mechanisms by which scl isoforms regulate HSC development. ..
- Watson O, Novodvorsky P, Gray C, Rothman A, Lawrie A, Crossman D, et al. Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxic signalling. Cardiovasc Res. 2013;100:252-61 pubmed publisher..increased vascular Notch signalling in 48 h post-fertilization old embryos via up-regulation of the Notch ligand dll4. Despite this, patterning of the intersegmental vessels is not affected by absent blood flow...
- Therapontos C, Vargesson N. Zebrafish notch signalling pathway mutants exhibit trunk vessel patterning anomalies that are secondary to somite misregulation. Dev Dyn. 2010;239:2761-8 pubmed publisher..Ectopic filopodia were also observed on the ISVs of the mutants. Ectopic filopodia are not due to loss of dll4. Somite expression of known vascular guidance cues, efnb2, sema3a2, and plexinD1 are disrupted, suggesting that the ..
- Hsiao C, You M, Guh Y, Ma M, Jiang Y, Hwang P. A positive regulatory loop between foxi3a and foxi3b is essential for specification and differentiation of zebrafish epidermal ionocytes. PLoS ONE. 2007;2:e302 pubmed
- Carra S, Sangiorgio L, Pelucchi P, Cermenati S, Mezzelani A, Martino V, et al. Zebrafish Tmem230a cooperates with the Delta/Notch signaling pathway to modulate endothelial cell number in angiogenic vessels. J Cell Physiol. 2018;233:1455-1467 pubmed publisher..of endothelial cells induced by aberrant expression or inhibition of the activity of genes associated with the Dll4/Notch pathway in zebrafish. Therefore, Tmem230a may have a modulatory role in vessel-network formation and growth...
- Zhang C, Chen Y, Sun B, Wang L, Yang Y, Ma D, et al. m6A modulates haematopoietic stem and progenitor cell specification. Nature. 2017;549:273-276 pubmed publisher..Furthermore, knockdown of Mettl3 in mice confers a similar phenotype. Collectively, our findings demonstrate the critical function of m6A modification in the fate determination of HSPCs during vertebrate embryogenesis. ..
- Shin M, Beane T, Quillien A, Male I, Zhu L, Lawson N. Vegfa signals through ERK to promote angiogenesis, but not artery differentiation. Development. 2016;143:3796-3805 pubmed..caused a loss of genes implicated in coordinating tip/stalk cell behaviors, including flt4 and, at later stages, dll4 ERK inhibition also blocked excessive angiogenesis and ectopic flt4 expression in Notch-deficient blood vessels...
- Pendeville H, Winandy M, Manfroid I, Nivelles O, Motte P, Pasque V, et al. Zebrafish Sox7 and Sox18 function together to control arterial-venous identity. Dev Biol. 2008;317:405-16 pubmed publisher..The striking similarities between the phenotype of Sox7/Sox18 morphants and Gridlock mutants strongly suggest that Sox7 and Sox18 control arterial-venous identity by regulating Gridlock expression. ..
- Yan H, Zhang C, Wang Z, Tu T, Duan H, Luo Y, et al. CD146 is required for VEGF-C-induced lymphatic sprouting during lymphangiogenesis. Sci Rep. 2017;7:7442 pubmed publisher..Altogether, our data reveals a critical role of CD146 to mediate VEGF-C signaling pathway in lymphangiogenesis. ..
- Weijts B, van Impel A, Schulte Merker S, de Bruin A. Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4. PLoS ONE. 2013;8:e73693 pubmed publisher..Together these results identified E2f7/8 as novel in vivo transcriptional regulators of Ccbe1 and Flt4, both essential genes for venous sprouting and lymphangiogenesis. ..
- Zygmunt T, Gay C, Blondelle J, Singh M, Flaherty K, Means P, et al. Semaphorin-PlexinD1 signaling limits angiogenic potential via the VEGF decoy receptor sFlt1. Dev Cell. 2011;21:301-14 pubmed publisher..Hence, Sema-PlxnD1 signaling regulates distinct but related aspects of angiogenesis: the spatial allocation of angiogenic capacity within a primary vessel and sprout guidance. ..
- Chen X, Gays D, Milia C, Santoro M. Cilia Control Vascular Mural Cell Recruitment in Vertebrates. Cell Rep. 2017;18:1033-1047 pubmed publisher..In summary, we have identified a hemodynamic-dependent mechanism in the developing vasculature that controls vMC recruitment. ..
- Bower N, Vogrin A, Le Guen L, Chen H, Stacker S, Achen M, et al. Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development. Development. 2017;144:507-518 pubmed publisher..that vegfd and vegfc also redundantly drive artery hyperbranching phenotypes observed upon depletion of Flt1 or Dll4. Epistasis and biochemical binding assays suggest that, during primary angiogenesis, Vegfd influences these ..
- Swift M, Pham V, Castranova D, Bell K, Poole R, Weinstein B. SoxF factors and Notch regulate nr2f2 gene expression during venous differentiation in zebrafish. Dev Biol. 2014;390:116-25 pubmed publisher..We show that Notch signaling activity present in the dorsal aorta suppresses expression of nr2f2, restricting nr2f2-dependent promotion of venous differentiation to the cardinal vein. ..
- Montero Balaguer M, Swirsding K, Orsenigo F, Cotelli F, Mione M, Dejana E. Stable vascular connections and remodeling require full expression of VE-cadherin in zebrafish embryos. PLoS ONE. 2009;4:e5772 pubmed publisher..This suggests that partial internalization or change of function of this protein may strongly affect vascular stability and organization. ..
- Pan W, Pham V, Stratman A, Castranova D, Kamei M, Kidd K, et al. CDP-diacylglycerol synthetase-controlled phosphoinositide availability limits VEGFA signaling and vascular morphogenesis. Blood. 2012;120:489-98 pubmed publisher..These results suggest that availability of CDS-controlled resynthesis of phosphoinositides is essential for angiogenesis. ..
- Wilkinson R, Koudijs M, Patient R, Ingham P, Schulte Merker S, van Eeden F. Hedgehog signaling via a calcitonin receptor-like receptor can induce arterial differentiation independently of VEGF signaling in zebrafish. Blood. 2012;120:477-88 pubmed publisher..Finally, our experiments establish a dual function of Hh during induction of runx1(+) HSCs. ..
- Hogan B, Herpers R, Witte M, Helotera H, Alitalo K, Duckers H, et al. Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries. Development. 2009;136:4001-9 pubmed publisher..Recent studies have demonstrated a role for Flt4 in blood vessels and showed that Dll4 limits angiogenic potential by limiting Flt4 function in developing blood vessels...
- Rochon E, Wright D, Schubert M, Roman B. Context-specific interactions between Notch and ALK1 cannot explain ALK1-associated arteriovenous malformations. Cardiovasc Res. 2015;107:143-52 pubmed publisher..In contrast, Notch and Alk1 play opposing roles in hey2 expression in cranial arteries and dll4 expression in all arterial endothelium, with Notch inducing and Alk1 repressing these genes...
- So J, Kim J, Yoo K, Kim H, Jung S, Choi J, et al. FIH-1, a novel interactor of mindbomb, functions as an essential anti-angiogenic factor during zebrafish vascular development. PLoS ONE. 2014;9:e109517 pubmed publisher..Taken together, our data suggest that FIH-1 interacts with Mib E3 Ubiquitin ligase and modulates vascular development by attenuating VEGF-A signaling activity. ..
- Coxam B, Neyt C, Grassini D, Le Guen L, Smith K, Schulte Merker S, et al. carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (cad) regulates Notch signaling and vascular development in zebrafish. Dev Dyn. 2015;244:1-9 pubmed publisher..These findings suggest important posttranslational modifications requiring Cad as an unappreciated mechanism that regulates Notch/Vegf signaling during angiogenesis. ..
- Gore A, Athans B, Iben J, Johnson K, Russanova V, Castranova D, et al. Epigenetic regulation of hematopoiesis by DNA methylation. elife. 2016;5:e11813 pubmed publisher..Our results reveal an epigenetic mechanism supporting the maintenance of hematopoietic cell fate via DNA methylation-mediated perdurance of a key transcription factor in HSPCs. ..
- Okigawa S, Mizoguchi T, Okano M, Tanaka H, Isoda M, Jiang Y, et al. Different combinations of Notch ligands and receptors regulate V2 interneuron progenitor proliferation and V2a/V2b cell fate determination. Dev Biol. 2014;391:196-206 pubmed publisher..In conclusion, V2-IN cell progenitor proliferation and V2a/V2b cell fate determination involve signaling through different sets of Notch ligand-receptor combinations that occur concurrently during development in zebrafish. ..