Bussmann, Jeroen

Lawson, Nathan

Schulte-Merker, Stefan

Zebrafish Nomenclature Committee

Zon, Leonard Ira

PLoS Genetics

Harvard University - DASH 

 Zebrafish VEGF Receptors: A Guideline to Nomenclature  (Article begins on next page)The Harvard community has made this article openly available.Please share how this access benefits you. Your story matters.Citation Bussmann, Jeroen, Nathan Lawson, Leonard Zon, Stefan Schulte-Merker, and Zebrafish Nomenclature Committee. 2008. ZebrafishVEGF Receptors: A Guideline to Nomenclature. PLoS Genetics 4:e1000064.Published Version doi:10.1371/journal.pgen.1000064Accessed February 18, 2015 11:05:30 PM ESTCitable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11181166Terms of Use This article was downloaded from Harvard University's DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth athttp://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAASpecial ReportZebrafish VEGF Receptors: A Guideline to NomenclatureJeroen Bussmann1, Nathan Lawson2, Leonard Zon3, Stefan Schulte-Merker4*, Zebrafish NomenclatureCommittee51Hubrecht Laboratory (NIOB-KNAW NIOB), Utrecht, The Netherlands, 2University of Massachusetts Medical School, Worcester, Massachusetts, United States of America,3Harvard Medical School and Children’s Hospital Pediatrics, Cambridge, Massachusetts, United States of America, 4Hubrecht Laboratory (NIOB-KNAW NIOB), Utrecht, TheNetherlands, 5Marc Ekker, Center for Advanced Research in Environmental Genomics, University of Ottawa, Ontario, Canada; Mary Mullins, Department of Cell andDevelopmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; John Postlethwait, Institute of Neuroscience, University ofOregon, Eugene, Oregon, United States of America; Monte Westerfield, Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States of AmericaIntroductionIn placental mammals (eutherians),there exist three paralogous genes of thevascular endothelial growth factor (VEGF)receptor family, namely FLT1 (also namedVEGFR1), KDR (also named FLK1 andVEGFR2), and FLT4 (also namedVEGFR3). Recent analysis of the VEGFreceptor repertoire in basally divergingvertebrates has identified a fourth repre-sentative of this gene family, which wassecondarily lost within the eutherianlineage, but is still present in marsupialsand platypus (monotremata). Because thisfourth member was initially described asan orthologue of the human KDR gene inzebrafish, confusion has arisen regardingthe evolutionary relationships of vertebrateVEGF receptors. Here, we revise thenomenclature of zebrafish VEGF recep-tors and name the fourth vertebrateVEGF receptor gene kdr-like.The members of the VEGF family ofligands, among them VEGF-A, VEGF-B,and VEGF-C, mediate cellular responsesby binding their cognate receptors. Thereceptors, which belong to the type IIIreceptor tyrosine kinase family, are single-pass transmembrane proteins containingseven extracellular immunoglobulin do-mains and a split intracellular tyrosinekinase domain. In human, mouse, andother mammals, three VEGF receptorshave been identified, namely FLT1 (alsonamed VEGFR1), KDR (also namedFLK1 and VEGFR2), and FLT4 (alsonamed VEGFR3).Since their initial identification in mam-mals, proteins homologous to VEGFRshave been identified in several basallydiverging vertebrates, including birds[1,2], amphibians [3], and teleost fish. Inthe zebrafish, four genes encoding VEGFreceptor proteins have been identified: theFLT1 orthologue [4,5], the FLT4 ortho-logue [6], and two genes with highestsimilarity to KDR/Flk1. The first of theseto be cloned [6–9] and functionallycharacterized [10] has been used in morethan 80 papers as a marker of endothelialCitation: Bussmann J, Lawson N, Zon L, Schulte-Merker S, Zebrafish Nomenclature Committee (2008) ZebrafishVEGF Receptors: A Guideline to Nomenclature. PLoS Genet 4(5): e1000064. doi:10.1371/journal.pgen.1000064Published May 30, 2008Copyright:  2008 Bussmann et al. This is an open-access article distributed under the terms of the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.Competing Interests: The authors have declared that no competing interests exist.* E-mail: s.schulte@niob.know.nlEditor: Wayne N. Frankel, The Jackson Laboratory, United States of AmericaFigure 1. Adapted from Bussmann et al., 2007 [4]. A. Unrooted neighbor-joining tree ofvertebrate VEGF receptors. Different colors represent different classes of VEGF receptors. Purpleshading was used to highlight the fourth vertebrate VEGF receptor class, which is missing ineutherian mammals. The node representing this fourth class was supported in 1000/1000bootstrap replicates. B. Synteny analysis of vertebrate VEGF receptors in the human, mouse, chick,and zebrafish genome assemblies. Different classes in A and B are colored similarly. Dashed linesrepresent synteny breaks in the Flt4 loci. Brackets indicate previously suggested names.doi:10.1371/journal.pgen.1000064.g001PLoS Genetics | www.plosgenetics.org 1 May 2008 | Volume 4 | Issue 5 | e1000064cells in the zebrafish and was originallynamed as the zebrafish orthologue ofKDR/FLK1. However, the recent identi-fication of a second potential KDR/FLK1orthologue [4,11,12], which in fact is moresimilar to the human gene, has causedconfusion over the evolutionary relation-ships of zebrafish and mammalian VEGFreceptors.In many cases, the presence of twozebrafish orthologues of a single humangene can be attributed to a whole-genomeduplication event that occurred within theteleost lineage. It was therefore hypothe-sized that zebrafish contains duplicatedKDR genes, which were consequentlycalled kdra (the gene originally called flk1)and kdrb (the gene that is most similar tohuman KDR). However, two lines ofevidence have recently challenged thisview [4,13–15] and rather suggest thatthis is a case of ‘‘ohnologs’’ [16,17]. First,VEGF receptor sequences that were mostsimilar to zebrafish flk1/kdra were identi-fied, not only in the genomes of otherteleosts, but also in the genomes of highervertebrates, such as Xenopus, chicken,platypus, and opossum. Phylogenetic anal-ysis of these genes, together with otherVEGF receptor sequences, clearly showedthat they cluster as a separate class(Figure 1A). Second, synteny analysisshowed that the loci containing the zebra-fish flk1/kdra and kdrb have been con-served throughout vertebrate evolution(Figure 1B), strongly indicating the pres-ence of both genes in the commonancestor of fish and mammals and theloss of a fourth VEGF receptor in theeutherian lineage (after the divergence ofmarsupial and placental mammals).Although representing separate classes,experimental data revealed significantfunctional similarity of zebrafish flk1/kdraand kdrb. Both genes are expressed in allendothelial cells, whereas flt1 and flt4 havea more restricted expression. Furthermore,zebrafish VEGF can bind and activateboth flk1/kdra and kdrb [11]. Finally, flk1/kdra and kdrb genetically interact: knock-down of kdrb in a flk1/kdra mutantbackground resulted in similar phenotypesas those observed in embryos in which vegfwas knocked down or in which a down-stream signaling component, phospholipase-cc1, is mutated ([12] and N. Lawson,unpublished data).ConclusionTherefore, to reflect that flk1/kdra is aprominent receptor in VEGF-A signalingin zebrafish, while at the same timeindicating that it represents a fourth classof vertebrate VEGF receptors (and is notthe result of a teleost gene duplication), wepropose to rename this gene kdr-like. As thezebrafish kdrb gene is clearly orthologousto mammalian KDR, we propose torename this gene kdr.AcknowledgmentsWe apologize to those authors whose work wewere unable to cite for space reasons.References1. Marcelle C, Eichmann A (1992) Molecularcloning of a family of protein kinase genesexpressed in the avian embryo. Oncogene 7:2479–2487.2. Sugishita Y, Takahashi T, Shimizu T, Yao A,Kinugawa K, et al. (2000) Expression of genesencoding vascular endothelial growth factor andits Flk-1 receptor in the chick embryonic heart.Mol Cell Cardiol 32: 1039–1051.3. Cleaver O, Tonissen KF, Saha MS, Krieg PA(1997) Neovascularization of the Xenopus em-bryo. Dev Dyn 210: 66–77.4. Bussmann J, Bakkers J, Schulte-Merker S (2007)Early endocardial morphogenesis requires Scl/Tal1. PLoS Genet 3: e140. doi:10.1371/journal.pgen.0030140.5. Rottbauer W, Just S, Wessels G, Trano N, Most P,et al. (2005) VEGF-PLCgamma1 pathway con-trols cardiac contractility in the embryonic heart.Genes Dev 19: 1624–1634.6. Thompson MA, Ransom DG, Pratt SJ,MacLennan H, Kieran MW, et al. (1998) Thecloche and spadetail genes differentially affecthematopoiesis and vasculogenesis. Dev Biol 197:248–269.7. Fouquet B, Weinstein BM, Serluca FC,Fishman MC (1997) Vessel patterning in theembryo of the zebrafish: guidance by notochord.Dev Biol 183: 37–48.8. Liao W, Bisgrove BW, Sawyer H, Hug B, Bell B,et al. (1997) The zebrafish gene cloche actsupstream of a flk-1 homologue to regulateendothelial cell differentiation. Development124: 381–389.9. Sumoy L, Keasey JB, Dittman TD, Kimelman D(1997) A role for notochord in axial vasculardevelopment revealed by analysis of phenotypeand the expression of VEGR-2 in zebrafish flhand ntl mutant embryos. Mech Dev 63: 15–27.10. Habeck HA, Odenthal J, Walderich B,Maischein HM, Schulte-Merker S (2002) Anal-ysis of a zebrafish VEGF receptor mutant revealsspecific disruption of angiogenesis. Curr Biol 12:1405–1412.11. Bahary N, Goishi K, Stuckenholz C, Weber G,Leblanc J, et al. (2007) Duplicate VegfA genesand orthologues of the KDR receptor tyrosinekinase family mediate vascular development inthe zebrafish. Blood 110: 3627–3636.12. Covassin LD, Villefranc JA, Kacergis MC,Weinstein BM, Lawson ND (2006) Distinctgenetic interactions between multiple Vegf recep-tors are required for development of differentblood vessel types in zebrafish. Proc Natl AcadSci U S A 103: 6554–6559.13. Mulley JF, Chiu CH, Holland PW (2006)Breakup of a homeobox cluster after genomeduplication in teleosts. Proc Natl Acad Sci U S A103: 10369–10372.14. Prohaska SJ, Stadler PF (2006) Evolution of thevertebrate ParaHox clusters. J Exp Zoolog B MolDev Evol 306: 481–487.15. Siegel N, Hoegg S, Salzburger W, Braasch I,Meyer A (2007) Comparative genomics ofParaHox clusters of teleost fishes: gene clusterbreakup and the retention of gene sets followingwhole genome duplications. BMC Genomics 8:312.16. Postlethwait JH (2006) The zebrafish genome incontext: Ohnologs gone missing. J Exp Zool MolDev Evol 308: 563–577.17. Wolfe K (2000) Robustness: it’s not where youthink it is. Nat Genet 25: 3–4.PLoS Genetics | www.plosgenetics.org 2 May 2008 | Volume 4 | Issue 5 | e1000064

Zebrafish VEGF Receptors: A Guideline to Nomenclature

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Zebrafish VEGF Receptors: A Guideline to Nomenclature

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