Advertisement

Interrogating Cardiovascular Genetics in Zebrafish

  • Jiandong Liu
  • Marc Renz
  • David Hassel
Chapter
Part of the Cardiac and Vascular Biology book series (Abbreviated title: Card. vasc. biol., volume 7)

Abstract

Emerged as a highly versatile and applicable vertebrate animal model to study embryonic development, zebrafish over the last two decades became a valuable human disease model for cardiovascular research. The unprecedented in vivo imaging capabilities allowing live analysis of organ formation and organ function combined with the ease of precise genetic interrogation established zebrafish as a recognized cardiovascular disease model. This chapter provides an overview of zebrafish’s history in biomedical and particularly cardiovascular research, delivers an outline of available methodologies and resources when using zebrafish, and gives examples of the versatility of zebrafish in cardiovascular research and how it progressed our understanding of a given disease.

Notes

Acknowledgments

We would like to thank the members of the Hassel and Liu lab for the vivid discussions and valuable input for the book chapter. We would further like to deeply thank all authors whose work we cited and at the same time apologize to all authors whose papers we could not reference due to space limitations. This work was supported by R56HL133081 to J.L.

References

  1. 1.
    Kimmel CB. Genetics and early development of zebrafish. Trends Genet. 1989;5:283–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Driever W, Solnica-Krezel L, Schier AF, Neuhauss SC, Malicki J, Stemple DL, Stainier DY, Zwartkruis F, Abdelilah S, Rangini Z, Belak J, Boggs C. A genetic screen for mutations affecting embryogenesis in zebrafish. Development. 1996;123:37–46.PubMedGoogle Scholar
  3. 3.
    Haffter P, Granato M, Brand M, Mullins MC, Hammerschmidt M, Kane DA, Odenthal J, van Eeden FJ, Jiang YJ, Heisenberg CP, Kelsh RN, Furutani-Seiki M, Vogelsang E, Beuchle D, Schach U, Fabian C, Nusslein-Volhard C. The identification of genes with unique and essential functions in the development of the zebrafish, danio rerio. Development. 1996;123:1–36.PubMedGoogle Scholar
  4. 4.
    Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF. Stages of embryonic development of the zebrafish. Dev Dyn. 1995;203:253–310.PubMedCrossRefGoogle Scholar
  5. 5.
    Stainier DY, Lee RK, Fishman MC. Cardiovascular development in the zebrafish. I. Myocardial fate map and heart tube formation. Development. 1993;119:31–40.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Just S, Meder B, Berger IM, Etard C, Trano N, Patzel E, Hassel D, Marquart S, Dahme T, Vogel B, Fishman MC, Katus HA, Strahle U, Rottbauer W. The myosin-interacting protein smyd1 is essential for sarcomere organization. J Cell Sci. 2011;124:3127–36.PubMedCrossRefGoogle Scholar
  7. 7.
    Wang H, Long Q, Marty SD, Sassa S, Lin S. A zebrafish model for hepatoerythropoietic porphyria. Nat Genet. 1998;20:239–43.PubMedCrossRefGoogle Scholar
  8. 8.
    Phillips JB, Westerfield M. Zebrafish models in translational research: tipping the scales toward advancements in human health. Dis Model Mech. 2014;7:739–43.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ablain J, Zon LI. Of fish and men: using zebrafish to fight human diseases. Trends Cell Biol. 2013;23:584–6.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Santoriello C, Zon LI. Hooked! Modeling human disease in zebrafish. J Clin Invest. 2012;122:2337–43.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Verkerk AO, Remme CA. Zebrafish: A novel research tool for cardiac (patho)electrophysiology and ion channel disorders. Front Physiol. 2012;3:255.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Davis EE, Frangakis S, Katsanis N. Interpreting human genetic variation with in vivo zebrafish assays. Biochim Biophys Acta. 1842;2014:1960–70.Google Scholar
  13. 13.
    Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C, Muffato M, Collins JE, Humphray S, McLaren K, Matthews L, McLaren S, Sealy I, Caccamo M, Churcher C, Scott C, Barrett JC, Koch R, Rauch GJ, White S, Chow W, Kilian B, Quintais LT, Guerra-Assuncao JA, Zhou Y, Gu Y, Yen J, Vogel JH, Eyre T, Redmond S, Banerjee R, Chi J, Fu B, Langley E, Maguire SF, Laird GK, Lloyd D, Kenyon E, Donaldson S, Sehra H, Almeida-King J, Loveland J, Trevanion S, Jones M, Quail M, Willey D, Hunt A, Burton J, Sims S, McLay K, Plumb B, Davis J, Clee C, Oliver K, Clark R, Riddle C, Elliot D, Threadgold G, Harden G, Ware D, Begum S, Mortimore B, Kerry G, Heath P, Phillimore B, Tracey A, Corby N, Dunn M, Johnson C, Wood J, Clark S, Pelan S, Griffiths G, Smith M, Glithero R, Howden P, Barker N, Lloyd C, Stevens C, Harley J, Holt K, Panagiotidis G, Lovell J, Beasley H, Henderson C, Gordon D, Auger K, Wright D, Collins J, Raisen C, Dyer L, Leung K, Robertson L, Ambridge K, Leongamornlert D, McGuire S, Gilderthorp R, Griffiths C, Manthravadi D, Nichol S, Barker G, Whitehead S, Kay M, Brown J, Murnane C, Gray E, Humphries M, Sycamore N, Barker D, Saunders D, Wallis J, Babbage A, Hammond S, Mashreghi-Mohammadi M, Barr L, Martin S, Wray P, Ellington A, Matthews N, Ellwood M, Woodmansey R, Clark G, Cooper J, Tromans A, Grafham D, Skuce C, Pandian R, Andrews R, Harrison E, Kimberley A, Garnett J, Fosker N, Hall R, Garner P, Kelly D, Bird C, Palmer S, Gehring I, Berger A, Dooley CM, Ersan-Urun Z, Eser C, Geiger H, Geisler M, Karotki L, Kirn A, Konantz J, Konantz M, Oberlander M, Rudolph-Geiger S, Teucke M, Lanz C, Raddatz G, Osoegawa K, Zhu B, Rapp A, Widaa S, Langford C, Yang F, Schuster SC, Carter NP, Harrow J, Ning Z, Herrero J, Searle SM, Enright A, Geisler R, Plasterk RH, Lee C, Westerfield M, de Jong PJ, Zon LI, Postlethwait JH, Nusslein-Volhard C, Hubbard TJ, Roest Crollius H, Rogers J, Stemple DL. The zebrafish reference genome sequence and its relationship to the human genome. Nature. 2013;496:498–503.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Postlethwait JH, Woods IG, Ngo-Hazelett P, Yan YL, Kelly PD, Chu F, Huang H, Hill-Force A, Talbot WS. Zebrafish comparative genomics and the origins of vertebrate chromosomes. Genome Res. 2000;10:1890–902.PubMedCrossRefGoogle Scholar
  15. 15.
    Amsterdam A, Hopkins N. Mutagenesis strategies in zebrafish for identifying genes involved in development and disease. Trends Genet. 2006;22:473–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Nagayoshi S, Hayashi E, Abe G, Osato N, Asakawa K, Urasaki A, Horikawa K, Ikeo K, Takeda H, Kawakami K. Insertional mutagenesis by the tol2 transposon-mediated enhancer trap approach generated mutations in two developmental genes: Tcf7 and synembryn-like. Development. 2008;135:159–69.PubMedCrossRefGoogle Scholar
  17. 17.
    Sivasubbu S, Balciunas D, Davidson AE, Pickart MA, Hermanson SB, Wangensteen KJ, Wolbrink DC, Ekker SC. Gene-breaking transposon mutagenesis reveals an essential role for histone h2afza in zebrafish larval development. Mech Dev. 2006;123:513–29.PubMedCrossRefGoogle Scholar
  18. 18.
    Gaiano N, Amsterdam A, Kawakami K, Allende M, Becker T, Hopkins N. Insertional mutagenesis and rapid cloning of essential genes in zebrafish. Nature. 1996;383:829–32.PubMedCrossRefGoogle Scholar
  19. 19.
    McGrail M, Hatler JM, Kuang X, Liao HK, Nannapaneni K, Watt KE, Uhl JD, Largaespada DA, Vollbrecht E, Scheetz TE, Dupuy AJ, Hostetter JM, Essner JJ. Somatic mutagenesis with a sleeping beauty transposon system leads to solid tumor formation in zebrafish. PLoS One. 2011;6:e18826.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Kramer C, Mayr T, Nowak M, Schumacher J, Runke G, Bauer H, Wagner DS, Schmid B, Imai Y, Talbot WS, Mullins MC, Hammerschmidt M. Maternally supplied smad5 is required for ventral specification in zebrafish embryos prior to zygotic bmp signaling. Dev Biol. 2002;250:263–79.PubMedCrossRefGoogle Scholar
  21. 21.
    Bai X, Kim J, Yang Z, Jurynec MJ, Akie TE, Lee J, LeBlanc J, Sessa A, Jiang H, DiBiase A, Zhou Y, Grunwald DJ, Lin S, Cantor AB, Orkin SH, Zon LI. Tif1gamma controls erythroid cell fate by regulating transcription elongation. Cell. 2010;142:133–43.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Asnani A, Peterson RT. The zebrafish as a tool to identify novel therapies for human cardiovascular disease. Dis Model Mech. 2014;7:763–7.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Bakkers J. Zebrafish as a model to study cardiac development and human cardiac disease. Cardiovasc Res. 2011;91:279–88.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Stainier DY, Fouquet B, Chen JN, Warren KS, Weinstein BM, Meiler SE, Mohideen MA, Neuhauss SC, Solnica-Krezel L, Schier AF, Zwartkruis F, Stemple DL, Malicki J, Driever W, Fishman MC. Mutations affecting the formation and function of the cardiovascular system in the zebrafish embryo. Development. 1996;123:285–92.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Thisse C, Thisse B. High-resolution in situ hybridization to whole-mount zebrafish embryos. Nat Protoc. 2008;3:59–69.PubMedCrossRefGoogle Scholar
  26. 26.
    Vogel G. Genomics. Sanger will sequence zebrafish genome. Science. 2000;290:1671.PubMedCrossRefGoogle Scholar
  27. 27.
    Rossi A, Kontarakis Z, Gerri C, Nolte H, Holper S, Kruger M, Stainier DY. Genetic compensation induced by deleterious mutations but not gene knockdowns. Nature. 2015;524:230–3.CrossRefPubMedGoogle Scholar
  28. 28.
    Wienholds E, van Eeden F, Kosters M, Mudde J, Plasterk RH, Cuppen E. Efficient target-selected mutagenesis in zebrafish. Genome Res. 2003;13:2700–7.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Sprague J, Doerry E, Douglas S, Westerfield M. The zebrafish information network (zfin): a resource for genetic, genomic and developmental research. Nucleic Acids Res. 2001;29:87–90.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Eisen JS, Smith JC. Controlling morpholino experiments: don’t stop making antisense. Development. 2008;135:1735–43.PubMedCrossRefGoogle Scholar
  31. 31.
    Nasevicius A, Ekker SC. Effective targeted gene ‘knockdown’ in zebrafish. Nat Genet. 2000;26:216–20.PubMedCrossRefGoogle Scholar
  32. 32.
    Draper BW, Morcos PA, Kimmel CB. Inhibition of zebrafish fgf8 pre-mrna splicing with morpholino oligos: a quantifiable method for gene knockdown. Genesis. 2001;30:154–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Shestopalov IA, Sinha S, Chen JK. Light-controlled gene silencing in zebrafish embryos. Nat Chem Biol. 2007;3:650–1.PubMedCrossRefGoogle Scholar
  34. 34.
    Ouyang X, Shestopalov IA, Sinha S, Zheng G, Pitt CL, Li WH, Olson AJ, Chen JK. Versatile synthesis and rational design of caged morpholinos. J Am Chem Soc. 2009;131:13255–69.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Montalbano A, Juergensen L, Roeth R, Weiss B, Fukami M, Fricke-Otto S, Binder G, Ogata T, Decker E, Nuernberg G, Hassel D, Rappold GA. Retinoic acid catabolizing enzyme cyp26c1 is a genetic modifier in shox deficiency. EMBO Mol Med. 2016;8:1455–69.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Hassel D, Cheng P, White MP, Ivey KN, Kroll J, Augustin HG, Katus HA, Stainier DY, Srivastava D. Microrna-10 regulates the angiogenic behavior of zebrafish and human endothelial cells by promoting vascular endothelial growth factor signaling. Circ Res. 2012;111:1421–33.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Choi WY, Giraldez AJ, Schier AF. Target protectors reveal dampening and balancing of nodal agonist and antagonist by mir-430. Science. 2007;318:271–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Blum M, De Robertis EM, Wallingford JB, Niehrs C. Morpholinos: antisense and sensibility. Dev Cell. 2015;35:145–9.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Kok FO, Shin M, Ni CW, Gupta A, Grosse AS, van Impel A, Kirchmaier BC, Peterson-Maduro J, Kourkoulis G, Male I, DeSantis DF, Sheppard-Tindell S, Ebarasi L, Betsholtz C, Schulte-Merker S, Wolfe SA, Lawson ND. Reverse genetic screening reveals poor correlation between morpholino-induced and mutant phenotypes in zebrafish. Dev Cell. 2015;32:97–108.PubMedCrossRefGoogle Scholar
  40. 40.
    Hwang WY, Fu Y, Reyon D, Maeder ML, Kaini P, Sander JD, Joung JK, Peterson RT, Yeh JR. Heritable and precise zebrafish genome editing using a crispr-cas system. PLoS One. 2013;8:e68708.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Chang N, Sun C, Gao L, Zhu D, Xu X, Zhu X, Xiong JW, Xi JJ. Genome editing with rna-guided cas9 nuclease in zebrafish embryos. Cell Res. 2013;23:465–72.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Sander JD, Cade L, Khayter C, Reyon D, Peterson RT, Joung JK, Yeh JR. Targeted gene disruption in somatic zebrafish cells using engineered talens. Nat Biotechnol. 2011;29:697–8.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Huang P, Xiao A, Zhou M, Zhu Z, Lin S, Zhang B. Heritable gene targeting in zebrafish using customized talens. Nat Biotechnol. 2011;29:699–700.PubMedCrossRefGoogle Scholar
  44. 44.
    Doyon Y, McCammon JM, Miller JC, Faraji F, Ngo C, Katibah GE, Amora R, Hocking TD, Zhang L, Rebar EJ, Gregory PD, Urnov FD, Amacher SL. Heritable targeted gene disruption in zebrafish using designed zinc-finger nucleases. Nat Biotechnol. 2008;26:702–8.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Kim YG, Cha J, Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to fok i cleavage domain. Proc Natl Acad Sci U S A. 1996;93:1156–60.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Narayanan A, Hill-Teran G, Moro A, Ristori E, Kasper DM, Roden CA, Lu J, Nicoli S. In vivo mutagenesis of mirna gene families using a scalable multiplexed crispr/cas9 nuclease system. Sci Rep. 2016;6:32386.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Kasper DM, Moro A, Ristori E, Narayanan A, Hill-Teran G, Fleming E, Moreno-Mateos M, Vejnar CE, Zhang J, Lee D, Gu M, Gerstein M, Giraldez A, Nicoli S. Micrornas establish uniform traits during the architecture of vertebrate embryos. Dev Cell. 2017;40:552–565 e555.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Albadri S, Del Bene F, Revenu C. Genome editing using crispr/cas9-based knock-in approaches in zebrafish. Methods. 2017;121–122:77–85.PubMedCrossRefGoogle Scholar
  49. 49.
    Won M, Dawid IB. Pcr artifact in testing for homologous recombination in genomic editing in zebrafish. PLoS One. 2017;12:e0172802.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kawakami K. Tol2: a versatile gene transfer vector in vertebrates. Genome Biol. 2007;8(Suppl 1):S7.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Hassel D, Dahme T, Erdmann J, Meder B, Huge A, Stoll M, Just S, Hess A, Ehlermann P, Weichenhan D, Grimmler M, Liptau H, Hetzer R, Regitz-Zagrosek V, Fischer C, Nurnberg P, Schunkert H, Katus HA, Rottbauer W. Nexilin mutations destabilize cardiac z-disks and lead to dilated cardiomyopathy. Nat Med. 2009;15:1281–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Wang X, Yu Q, Wu Q, Bu Y, Chang NN, Yan S, Zhou XH, Zhu X, Xiong JW. Genetic interaction between pku300 and fbn2b controls endocardial cell proliferation and valve development in zebrafish. J Cell Sci. 2013;126:1381–91.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Durst R, Sauls K, Peal DS, deVlaming A, Toomer K, Leyne M, Salani M, Talkowski ME, Brand H, Perrocheau M, Simpson C, Jett C, Stone MR, Charles F, Chiang C, Lynch SN, Bouatia-Naji N, Delling FN, Freed LA, Tribouilloy C, LeTourneau T, LeMarec H, Fernandez-Friera L, Solis J, Trujillano D, Ossowski S, Estivill X, Dina C, Bruneval P, Chester A, Schott JJ, Irvine KD, Mao Y, Wessels A, Motiwala T, Puceat M, Tsukasaki Y, Menick DR, Kasiganesan H, Nie X, Broome AM, Williams K, Johnson A, Markwald RR, Jeunemaitre X, Hagege A, Levine RA, Milan DJ, Norris RA, Slaugenhaupt SA. Mutations in dchs1 cause mitral valve prolapse. Nature. 2015;525:109–13.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Dina C, Bouatia-Naji N, Tucker N, Delling FN, Toomer K, Durst R, Perrocheau M, Fernandez-Friera L, Solis J, Investigators P, Le Tourneau T, Chen MH, Probst V, Bosse Y, Pibarot P, Zelenika D, Lathrop M, Hercberg S, Roussel R, Benjamin EJ, Bonnet F, Lo SH, Dolmatova E, Simonet F, Lecointe S, Kyndt F, Redon R, LeMarec H, Froguel P, Ellinor PT, Vasan RS, Bruneval P, Markwald RR, Norris RA, Milan DJ, Slaugenhaupt SA, Levine RA, Schott JJ, Hagege AA, MVP F, Jeunemaitre X, Leducq Transatlantic MN. Genetic association analyses highlight biological pathways underlying mitral valve prolapse. Nat Genet. 2015;47:1206–11.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Ding Y, Sun X, Huang W, Hoage T, Redfield M, Kushwaha S, Sivasubbu S, Lin X, Ekker S, Xu X. Haploinsufficiency of target of rapamycin attenuates cardiomyopathies in adult zebrafish. Circ Res. 2011;109:658–69.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Group CCHW. Meta-analysis of rare and common exome chip variants identifies s1pr4 and other loci influencing blood cell traits. Nat Genet. 2016;48:867–76.CrossRefGoogle Scholar
  57. 57.
    Smith KA, Joziasse IC, Chocron S, van Dinther M, Guryev V, Verhoeven MC, Rehmann H, van der Smagt JJ, Doevendans PA, Cuppen E, Mulder BJ, Ten Dijke P, Bakkers J. Dominant-negative alk2 allele associates with congenital heart defects. Circulation. 2009;119:3062–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39:1890–900.PubMedCrossRefGoogle Scholar
  59. 59.
    Bruneau BG. The developmental genetics of congenital heart disease. Nature. 2008;451:943–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Brown DR, Samsa LA, Qian L, Liu J. Advances in the study of heart development and disease using zebrafish. J Cardiovasc Dev Dis. 2016;3:13.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Samsa LA, Givens C, Tzima E, Stainier DY, Qian L, Liu J. Cardiac contraction activates endocardial notch signaling to modulate chamber maturation in zebrafish. Development. 2015;142:4080–91.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Lai SL, Yao WL, Tsao KC, Houben AJ, Albers HM, Ovaa H, Moolenaar WH, Lee SJ. Autotaxin/lpar3 signaling regulates kupffer’s vesicle formation and left-right asymmetry in zebrafish. Development. 2012;139:4439–48.PubMedCrossRefGoogle Scholar
  63. 63.
    Srivastava D. Making or breaking the heart: from lineage determination to morphogenesis. Cell. 2006;126:1037–48.PubMedCrossRefGoogle Scholar
  64. 64.
    Stainier DY. Zebrafish genetics and vertebrate heart formation. Nat Rev Genet. 2001;2:39–48.PubMedCrossRefGoogle Scholar
  65. 65.
    Liu J, Stainier DY. Zebrafish in the study of early cardiac development. Circ Res. 2012;110:870–4.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Glickman NS, Yelon D. Cardiac development in zebrafish: coordination of form and function. Semin Cell Dev Biol. 2002;13:507–13.PubMedCrossRefGoogle Scholar
  67. 67.
    Samsa LA, Yang B, Liu J. Embryonic cardiac chamber maturation: trabeculation, conduction, and cardiomyocyte proliferation. Am J Med Genet C Semin Med Genet. 2013;163C:157–68.PubMedCrossRefGoogle Scholar
  68. 68.
    Beis D, Bartman T, Jin SW, Scott IC, D’Amico LA, Ober EA, Verkade H, Frantsve J, Field HA, Wehman A, Baier H, Tallafuss A, Bally-Cuif L, Chen JN, Stainier DY, Jungblut B. Genetic and cellular analyses of zebrafish atrioventricular cushion and valve development. Development. 2005;132:4193–204.PubMedCrossRefGoogle Scholar
  69. 69.
    Scherz PJ, Huisken J, Sahai-Hernandez P, Stainier DY. High-speed imaging of developing heart valves reveals interplay of morphogenesis and function. Development. 2008;135:1179–87.PubMedCrossRefGoogle Scholar
  70. 70.
    Bisgrove BW, Snarr BS, Emrazian A, Yost HJ. Polaris and polycystin-2 in dorsal forerunner cells and kupffer’s vesicle are required for specification of the zebrafish left-right axis. Dev Biol. 2005;287:274–88.PubMedCrossRefGoogle Scholar
  71. 71.
    Vetrini F, D'Alessandro LC, Akdemir ZC, Braxton A, Azamian MS, Eldomery MK, Miller K, Kois C, Sack V, Shur N, Rijhsinghani A, Chandarana J, Ding Y, Holtzman J, Jhangiani SN, Muzny DM, Gibbs RA, Eng CM, Hanchard NA, Harel T, Rosenfeld JA, Belmont JW, Lupski JR, Yang Y. Bi-allelic mutations in pkd1l1 are associated with laterality defects in humans. Am J Hum Genet. 2016;99:886–93.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Paffett-Lugassy N, Singh R, Nevis KR, Guner-Ataman B, O'Loughlin E, Jahangiri L, Harvey RP, Burns CG, Burns CE. Heart field origin of great vessel precursors relies on nkx2.5-mediated vasculogenesis. Nat Cell Biol. 2013;15:1362–9.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Nagelberg D, Wang J, Su R, Torres-Vazquez J, Targoff KL, Poss KD, Knaut H. Origin, specification, and plasticity of the great vessels of the heart. Curr Biol. 2015;25:2099–110.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Barron DJ, Kilby MD, Davies B, Wright JG, Jones TJ, Brawn WJ. Hypoplastic left heart syndrome. Lancet. 2009;374:551–64.PubMedCrossRefGoogle Scholar
  75. 75.
    Noonan JA, Nadas AS. The hypoplastic left heart syndrome; an analysis of 101 cases. Pediatr Clin N Am. 1958;5:1029–56.CrossRefGoogle Scholar
  76. 76.
    Norwood WI, Lang P, Hansen DD. Physiologic repair of aortic atresia-hypoplastic left heart syndrome. N Engl J Med. 1983;308:23–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Hinton RB, Martin LJ, Rame-Gowda S, Tabangin ME, Cripe LH, Benson DW. Hypoplastic left heart syndrome links to chromosomes 10q and 6q and is genetically related to bicuspid aortic valve. J Am Coll Cardiol. 2009;53:1065–71.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Dasgupta C, Martinez AM, Zuppan CW, Shah MM, Bailey LL, Fletcher WH. Identification of connexin43 (alpha1) gap junction gene mutations in patients with hypoplastic left heart syndrome by denaturing gradient gel electrophoresis (dgge). Mutat Res. 2001;479:173–86.PubMedCrossRefGoogle Scholar
  79. 79.
    Iascone M, Ciccone R, Galletti L, Marchetti D, Seddio F, Lincesso AR, Pezzoli L, Vetro A, Barachetti D, Boni L, Federici D, Soto AM, Comas JV, Ferrazzi P, Zuffardi O. Identification of de novo mutations and rare variants in hypoplastic left heart syndrome. Clin Genet. 2012;81:542–54.PubMedCrossRefGoogle Scholar
  80. 80.
    Targoff KL, Colombo S, George V, Schell T, Kim SH, Solnica-Krezel L, Yelon D. Nkx genes are essential for maintenance of ventricular identity. Development. 2013;140:4203–13.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Targoff KL, Schell T, Yelon D. Nkx genes regulate heart tube extension and exert differential effects on ventricular and atrial cell number. Dev Biol. 2008;322:314–21.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Liu X, Yagi H, Saeed S, Bais AS, Gabriel GC, Chen Z, Peterson KA, Li Y, Schwartz MC, Reynolds WT, Saydmohammed M, Gibbs B, Wu Y, Devine W, Chatterjee B, Klena NT, Kostka D, de Mesy Bentley KL, Ganapathiraju MK, Dexheimer P, Leatherbury L, Khalifa O, Bhagat A, Zahid M, Pu W, Watkins S, Grossfeld P, Murray SA, Porter GA Jr, Tsang M, Martin LJ, Benson DW, Aronow BJ, Lo CW. The complex genetics of hypoplastic left heart syndrome. Nat Genet. 2017;49:1152–9.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Renz M, Otten C, Faurobert E, Rudolph F, Zhu Y, Boulday G, Duchene J, Mickoleit M, Dietrich AC, Ramspacher C, Steed E, Manet-Dupe S, Benz A, Hassel D, Vermot J, Huisken J, Tournier-Lasserve E, Felbor U, Sure U, Albiges-Rizo C, Abdelilah-Seyfried S. Regulation of beta1 integrin-klf2-mediated angiogenesis by ccm proteins. Dev Cell. 2015;32:181–90.PubMedCrossRefGoogle Scholar
  84. 84.
    Fang L, Green SR, Baek JS, Lee SH, Ellett F, Deer E, Lieschke GJ, Witztum JL, Tsimikas S, Miller YI. In vivo visualization and attenuation of oxidized lipid accumulation in hypercholesterolemic zebrafish. J Clin Invest. 2011;121:4861–9.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Markwald RR, Norris RA, Moreno-Rodriguez R, Levine RA. Developmental basis of adult cardiovascular diseases: valvular heart diseases. Ann N Y Acad Sci. 2010;1188:177–83.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP III, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM III, Thomas JD, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Creager MA, Curtis LH, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Stevenson WG, Yancy CW, American College of C, American College of Cardiology/American Heart A, American Heart A. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J thorac Cardiovasc Surg. 2014;148:e1–e132.CrossRefGoogle Scholar
  87. 87.
    Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP III, Fleisher LA, Jneid H, Mack MJ, McLeod CJ, O’Gara PT, Rigolin VH, Sundt TM III, Thompson A. 2017 AHA/ACC focused update of the 2014 aha/acc guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2017;70:252–89.CrossRefGoogle Scholar
  88. 88.
    Staudt D, Stainier D. Uncovering the molecular and cellular mechanisms of heart development using the zebrafish. Annu Rev Genet. 2012;46:397–418.PubMedCrossRefGoogle Scholar
  89. 89.
    Pestel J, Ramadass R, Gauvrit S, Helker C, Herzog W, Stainier DY. Real-time 3d visualization of cellular rearrangements during cardiac valve formation. Development. 2016;143:2217–27.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Zhu L, Belmont JW, Ware SM. Genetics of human heterotaxias. Eur J Hum Genet. 2006;14:17–25.PubMedCrossRefGoogle Scholar
  91. 91.
    Amula V, Ellsworth GL, Bratton SL, Arrington CB, Witte MK. Heterotaxy syndrome: impact of ventricular morphology on resource utilization. Pediatr Cardiol. 2014;35:38–46.PubMedCrossRefGoogle Scholar
  92. 92.
    Unolt M, Putotto C, Silvestri LM, Marino D, Scarabotti A, Valerio M, Caiaro A, Versacci P, Marino B. Transposition of great arteries: new insights into the pathogenesis. Front Pediatr. 2013;1:11.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Lin AE, Krikov S, Riehle-Colarusso T, Frias JL, Belmont J, Anderka M, Geva T, Getz KD, Botto LD. National Birth Defects Prevention S. Laterality defects in the national birth defects prevention study (1998–2007): birth prevalence and descriptive epidemiology. Am J Med Genet A. 2014;164A:2581–91.PubMedCrossRefGoogle Scholar
  94. 94.
    Pennekamp P, Menchen T, Dworniczak B, Hamada H. Situs inversus and ciliary abnormalities: 20 years later, what is the connection? Cilia. 2015;4:1.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Kennedy MP, Omran H, Leigh MW, Dell S, Morgan L, Molina PL, Robinson BV, Minnix SL, Olbrich H, Severin T, Ahrens P, Lange L, Morillas HN, Noone PG, Zariwala MA, Knowles MR. Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation. 2007;115:2814–21.PubMedCrossRefGoogle Scholar
  96. 96.
    Nakhleh N, Francis R, Giese RA, Tian X, Li Y, Zariwala MA, Yagi H, Khalifa O, Kureshi S, Chatterjee B, Sabol SL, Swisher M, Connelly PS, Daniels MP, Srinivasan A, Kuehl K, Kravitz N, Burns K, Sami I, Omran H, Barmada M, Olivier K, Chawla KK, Leigh M, Jonas R, Knowles M, Leatherbury L, Lo CW. High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation. 2012;125:2232–42.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Li Y, Yagi H, Onuoha EO, Damerla RR, Francis R, Furutani Y, Tariq M, King SM, Hendricks G, Cui C, Saydmohammed M, Lee DM, Zahid M, Sami I, Leatherbury L, Pazour GJ, Ware SM, Nakanishi T, Goldmuntz E, Tsang M, Lo CW. Dnah6 and its interactions with pcd genes in heterotaxy and primary ciliary dyskinesia. PLoS Genet. 2016;12:e1005821.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Ostrowski LE, Dutcher SK, Lo CW. Cilia and models for studying structure and function. Proc Am Thorac Soc. 2011;8:423–9.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Guimier A, Gabriel GC, Bajolle F, Tsang M, Liu H, Noll A, Schwartz M, El Malti R, Smith LD, Klena NT, Jimenez G, Miller NA, Oufadem M, Moreau de Bellaing A, Yagi H, Saunders CJ, Baker CN, Di Filippo S, Peterson KA, Thiffault I, Bole-Feysot C, Cooley LD, Farrow EG, Masson C, Schoen P, Deleuze JF, Nitschke P, Lyonnet S, de Pontual L, Murray SA, Bonnet D, Kingsmore SF, Amiel J, Bouvagnet P, Lo CW, Gordon CT. Mmp21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates. Nat Genet. 2015;47:1260–3.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Xu X, Meiler SE, Zhong TP, Mohideen M, Crossley DA, Burggren WW, Fishman MC. Cardiomyopathy in zebrafish due to mutation in an alternatively spliced exon of titin. Nat Genet. 2002;30:205–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Sehnert AJ, Huq A, Weinstein BM, Walker C, Fishman M, Stainier DY. Cardiac troponin t is essential in sarcomere assembly and cardiac contractility. Nat Genet. 2002;31:106–10.PubMedCrossRefGoogle Scholar
  102. 102.
    Siu BL, Niimura H, Osborne JA, Fatkin D, MacRae C, Solomon S, Benson DW, Seidman JG, Seidman CE. Familial dilated cardiomyopathy locus maps to chromosome 2q31. Circulation. 1999;99:1022–6.PubMedCrossRefGoogle Scholar
  103. 103.
    Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE. Alpha-tropomyosin and cardiac troponin t mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994;77:701–12.PubMedCrossRefGoogle Scholar
  104. 104.
    Shih YH, Zhang Y, Ding Y, Ross CA, Li H, Olson TM, Xu X. Cardiac transcriptome and dilated cardiomyopathy genes in zebrafish. Circ Cardiovasc Genet. 2015;8:261–9.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Wang H, Li Z, Wang J, Sun K, Cui Q, Song L, Zou Y, Wang X, Liu X, Hui R, Fan Y. Mutations in nexn, a z-disc gene, are associated with hypertrophic cardiomyopathy. Am J Hum Genet. 2010;87:687–93.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Vogel B, Meder B, Just S, Laufer C, Berger I, Weber S, Katus HA, Rottbauer W. In-vivo characterization of human dilated cardiomyopathy genes in zebrafish. Biochem Biophys Res Commun. 2009;390:516–22.PubMedCrossRefGoogle Scholar
  107. 107.
    Ramspacher C, Steed E, Boselli F, Ferreira R, Faggianelli N, Roth S, Spiegelhalter C, Messaddeq N, Trinh L, Liebling M, Chacko N, Tessadori F, Bakkers J, Laporte J, Hnia K, Vermot J. Developmental alterations in heart biomechanics and skeletal muscle function in desmin mutants suggest an early pathological root for desminopathies. Cell Rep. 2015;11:1564–76.PubMedCrossRefGoogle Scholar
  108. 108.
    Liu J, Bressan M, Hassel D, Huisken J, Staudt D, Kikuchi K, Poss KD, Mikawa T, Stainier DY. A dual role for erbb2 signaling in cardiac trabeculation. Development. 2010;137:3867–75.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Meder B, Laufer C, Hassel D, Just S, Marquart S, Vogel B, Hess A, Fishman MC, Katus HA, Rottbauer W. A single serine in the carboxyl terminus of cardiac essential myosin light chain-1 controls cardiomyocyte contractility in vivo. Circ Res. 2009;104:650–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Bendig G, Grimmler M, Huttner IG, Wessels G, Dahme T, Just S, Trano N, Katus HA, Fishman MC, Rottbauer W. Integrin-linked kinase, a novel component of the cardiac mechanical stretch sensor, controls contractility in the zebrafish heart. Genes Dev. 2006;20:2361–72.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Rottbauer W, Just S, Wessels G, Trano N, Most P, Katus HA, Fishman MC. Vegf-plcgamma1 pathway controls cardiac contractility in the embryonic heart. Genes Dev. 2005;19:1624–34.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Zou J, Tran D, Baalbaki M, Tang LF, Poon A, Pelonero A, Titus EW, Yuan C, Shi C, Patchava S, Halper E, Garg J, Movsesyan I, Yin C, Wu R, Wilsbacher LD, Liu J, Hager RL, Coughlin SR, Jinek M, Pullinger CR, Kane JP, Hart DO, Kwok PY, Deo RC. An internal promoter underlies the difference in disease severity between n- and c-terminal truncation mutations of titin in zebrafish. elife. 2015;4:e09406.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Kossack M, Hein S, Juergensen L, Siragusa M, Benz A, Katus HA, Most P, Hassel D. Induction of cardiac dysfunction in developing and adult zebrafish by chronic isoproterenol stimulation. J Mol Cell Cardiol. 2017;108:95–105.PubMedCrossRefGoogle Scholar
  114. 114.
    Kalogirou S, Malissovas N, Moro E, Argenton F, Stainier DY, Beis D. Intracardiac flow dynamics regulate atrioventricular valve morphogenesis. Cardiovasc Res. 2014;104:49–60.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Asimaki A, Kapoor S, Plovie E, Karin Arndt A, Adams E, Liu Z, James CA, Judge DP, Calkins H, Churko J, Wu JC, MacRae CA, Kleber AG, Saffitz JE. Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy. Sci Transl Med. 2014;6:240ra274.CrossRefGoogle Scholar
  116. 116.
    Ding Y, Sun X, Xu X. Tor-autophagy signaling in adult zebrafish models of cardiomyopathy. Autophagy. 2012;8:142–3.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Sun X, Hoage T, Bai P, Ding Y, Chen Z, Zhang R, Huang W, Jahangir A, Paw B, Li YG, Xu X. Cardiac hypertrophy involves both myocyte hypertrophy and hyperplasia in anemic zebrafish. PLoS One. 2009;4:e6596.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Scheid LM, Mosqueira M, Hein S, Kossack M, Juergensen L, Mueller M, Meder B, Fink RH, Katus HA, Hassel D. Essential light chain s195 phosphorylation is required for cardiac adaptation under physical stress. Cardiovasc Res. 2016;111:44–55.PubMedCrossRefGoogle Scholar
  119. 119.
    Wang LW, Huttner IG, Santiago CF, Kesteven SH, Yu ZY, Feneley MP, Fatkin D. Standardized echocardiographic assessment of cardiac function in normal adult zebrafish and heart disease models. Dis Model Mech. 2017;10:63–76.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Hein SJ, Lehmann LH, Kossack M, Juergensen L, Fuchs D, Katus HA, Hassel D. Advanced echocardiography in adult zebrafish reveals delayed recovery of heart function after myocardial cryoinjury. PLoS One. 2015;10:e0122665.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Rottbauer W, Baker K, Wo ZG, Mohideen MA, Cantiello HF, Fishman MC. Growth and function of the embryonic heart depend upon the cardiac-specific l-type calcium channel alpha1 subunit. Dev Cell. 2001;1:265–75.PubMedCrossRefGoogle Scholar
  122. 122.
    Arnaout R, Ferrer T, Huisken J, Spitzer K, Stainier DY, Tristani-Firouzi M, Chi NC. Zebrafish model for human long qt syndrome. Proc Natl Acad Sci U S A. 2007;104:11316–21.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Langheinrich U, Vacun G, Wagner T. Zebrafish embryos express an orthologue of herg and are sensitive toward a range of qt-prolonging drugs inducing severe arrhythmia. Toxicol Appl Pharmacol. 2003;193:370–82.PubMedCrossRefGoogle Scholar
  124. 124.
    Milan DJ, Kim AM, Winterfield JR, Jones IL, Pfeufer A, Sanna S, Arking DE, Amsterdam AH, Sabeh KM, Mably JD, Rosenbaum DS, Peterson RT, Chakravarti A, Kaab S, Roden DM, MacRae CA. Drug-sensitized zebrafish screen identifies multiple genes, including gins3, as regulators of myocardial repolarization. Circulation. 2009;120:553–9.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Peal DS, Mills RW, Lynch SN, Mosley JM, Lim E, Ellinor PT, January CT, Peterson RT, Milan DJ. Novel chemical suppressors of long qt syndrome identified by an in vivo functional screen. Circulation. 2011;123:23–30.PubMedCrossRefGoogle Scholar
  126. 126.
    Hassel D, Scholz EP, Trano N, Friedrich O, Just S, Meder B, Weiss DL, Zitron E, Marquart S, Vogel B, Karle CA, Seemann G, Fishman MC, Katus HA, Rottbauer W. Deficient zebrafish ether-a-go-go-related gene channel gating causes short-qt syndrome in zebrafish reggae mutants. Circulation. 2008;117:866–75.PubMedCrossRefGoogle Scholar
  127. 127.
    Langenbacher AD, Dong Y, Shu X, Choi J, Nicoll DA, Goldhaber JI, Philipson KD, Chen JN. Mutation in sodium-calcium exchanger 1 (ncx1) causes cardiac fibrillation in zebrafish. Proc Natl Acad Sci U S A. 2005;102:17699–704.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Ebert AM, Hume GL, Warren KS, Cook NP, Burns CG, Mohideen MA, Siegal G, Yelon D, Fishman MC, Garrity DM. Calcium extrusion is critical for cardiac morphogenesis and rhythm in embryonic zebrafish hearts. Proc Natl Acad Sci U S A. 2005;102:17705–10.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Huttner IG, Trivedi G, Jacoby A, Mann SA, Vandenberg JI, Fatkin D. A transgenic zebrafish model of a human cardiac sodium channel mutation exhibits bradycardia, conduction-system abnormalities and early death. J Mol Cell Cardiol. 2013;61:123–32.PubMedCrossRefGoogle Scholar
  130. 130.
    Chen X, Gays D, Milia C, Santoro MM. Cilia control vascular mural cell recruitment in vertebrates. Cell Rep. 2017;18:1033–47.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Ando K, Fukuhara S, Izumi N, Nakajima H, Fukui H, Kelsh RN, Mochizuki N. Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish. Development. 2016;143:1328–39.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Karpanen T, Schulte-Merker S. Zebrafish provides a novel model for lymphatic vascular research. Methods Cell Biol. 2011;105:223–38.PubMedCrossRefGoogle Scholar
  133. 133.
    Santoro MM, Pesce G, Stainier DY. Characterization of vascular mural cells during zebrafish development. Mech Dev. 2009;126:638–49.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Jin SW, Beis D, Mitchell T, Chen JN, Stainier DY. Cellular and molecular analyses of vascular tube and lumen formation in zebrafish. Development. 2005;132:5199–209.PubMedCrossRefGoogle Scholar
  135. 135.
    Siekmann AF, Lawson ND. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature. 2007;445:781–4.PubMedCrossRefGoogle Scholar
  136. 136.
    Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C. Dll4 signalling through notch1 regulates formation of tip cells during angiogenesis. Nature. 2007;445:776–80.PubMedCrossRefGoogle Scholar
  137. 137.
    Herbert SP, Huisken J, Kim TN, Feldman ME, Houseman BT, Wang RA, Shokat KM, Stainier DY. Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation. Science. 2009;326:294–8.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Xu B, Zhang Y, Du XF, Li J, Zi HX, Bu JW, Yan Y, Han H, Du JL. Neurons secrete mir-132-containing exosomes to regulate brain vascular integrity. Cell Res. 2017;27:882–97.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Tobia C, Chiodelli P, Nicoli S, Dell'era P, Buraschi S, Mitola S, Foglia E, van Loenen PB, Alewijnse AE, Presta M. Sphingosine-1-phosphate receptor-1 controls venous endothelial barrier integrity in zebrafish. Arterioscler Thromb Vasc Biol. 2012;32:e104–16.PubMedCrossRefGoogle Scholar
  140. 140.
    Butler MG, Gore AV, Weinstein BM. Zebrafish as a model for hemorrhagic stroke. Methods Cell Biol. 2011;105:137–61.PubMedCrossRefGoogle Scholar
  141. 141.
    Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY, Srivastava D. Mir-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 2008;15:272–84.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Buchner DA, Su F, Yamaoka JS, Kamei M, Shavit JA, Barthel LK, McGee B, Amigo JD, Kim S, Hanosh AW, Jagadeeswaran P, Goldman D, Lawson ND, Raymond PA, Weinstein BM, Ginsburg D, Lyons SE. Pak2a mutations cause cerebral hemorrhage in redhead zebrafish. Proc Natl Acad Sci U S A. 2007;104:13996–4001.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Gu Y, Jin P, Zhang L, Zhao X, Gao X, Ning Y, Meng A, Chen YG. Functional analysis of mutations in the kinase domain of the tgf-beta receptor alk1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia. Blood. 2006;107:1951–4.PubMedCrossRefGoogle Scholar
  144. 144.
    Hall CJ, Flores MV, Davidson AJ, Crosier KE, Crosier PS. Radar is required for the establishment of vascular integrity in the zebrafish. Dev Biol. 2002;251:105–17.PubMedCrossRefGoogle Scholar
  145. 145.
    Liu J, Fraser SD, Faloon PW, Rollins EL, Vom Berg J, Starovic-Subota O, Laliberte AL, Chen JN, Serluca FC, Childs SJ. A betapix pak2a signaling pathway regulates cerebral vascular stability in zebrafish. Proc Natl Acad Sci U S A. 2007;104:13990–5.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Kleaveland B, Zheng X, Liu JJ, Blum Y, Tung JJ, Zou Z, Sweeney SM, Chen M, Guo L, Lu MM, Zhou D, Kitajewski J, Affolter M, Ginsberg MH, Kahn ML. Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway. Nat Med. 2009;15:169–76.PubMedCentralCrossRefPubMedGoogle Scholar
  147. 147.
    Gut P, Baeza-Raja B, Andersson O, Hasenkamp L, Hsiao J, Hesselson D, Akassoglou K, Verdin E, Hirschey MD, Stainier DY. Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism. Nat Chem Biol. 2013;9:97–104.PubMedCrossRefGoogle Scholar
  148. 148.
    Weger BD, Weger M, Nusser M, Brenner-Weiss G, Dickmeis T. A chemical screening system for glucocorticoid stress hormone signaling in an intact vertebrate. ACS Chem Biol. 2012;7:1178–83.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Stoletov K, Fang L, Choi SH, Hartvigsen K, Hansen LF, Hall C, Pattison J, Juliano J, Miller ER, Almazan F, Crosier P, Witztum JL, Klemke RL, Miller YI. Vascular lipid accumulation, lipoprotein oxidation, and macrophage lipid uptake in hypercholesterolemic zebrafish. Circ Res. 2009;104:952–60.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Swinney DC, Anthony J. How were new medicines discovered? Nat Rev Drug Discov. 2011;10:507–19.PubMedCrossRefGoogle Scholar
  151. 151.
    Eggert US. The why and how of phenotypic small-molecule screens. Nat Chem Biol. 2013;9:206–9.PubMedCrossRefGoogle Scholar
  152. 152.
    MacRae CA, Peterson RT. Zebrafish as tools for drug discovery. Nat Rev Drug Discov. 2015;14:721–31.PubMedCrossRefGoogle Scholar
  153. 153.
    Peterson RT, Link BA, Dowling JE, Schreiber SL. Small molecule developmental screens reveal the logic and timing of vertebrate development. Proc Natl Acad Sci U S A. 2000;97:12965–9.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Peterson RT, Shaw SY, Peterson TA, Milan DJ, Zhong TP, Schreiber SL, MacRae CA, Fishman MC. Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation. Nat Biotechnol. 2004;22:595–9.PubMedCrossRefGoogle Scholar
  155. 155.
    Zhong TP, Rosenberg M, Mohideen MA, Weinstein B, Fishman MC. Gridlock, an hlh gene required for assembly of the aorta in zebrafish. Science. 2000;287:1820–4.PubMedCrossRefGoogle Scholar
  156. 156.
    Weinstein BM, Stemple DL, Driever W, Fishman MC. Gridlock, a localized heritable vascular patterning defect in the zebrafish. Nat Med. 1995;1:1143–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Jiandong Liu
    • 1
    • 2
  • Marc Renz
    • 3
  • David Hassel
    • 3
  1. 1.McAllister Heart Institute, University of North Carolina at Chapel HillChapel HillUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.Department of Medicine III, Cardiology, Angiology, PneumologyUniversity Hospital HeidelbergHeidelbergGermany

Personalised recommendations