Development of the Dopamine Systems in Zebrafish

Part of the Advances in Experimental Medicine and Biology book series (volume 651)


Dopaminergic neurons develop in several distinct regions of the vertebrate brain and project locally or send long axonal projections to distant parts of the CNS to modulate the activity of a variety of circuits, controlling aspects of physiology, behavior and movement. The molecular control of dopaminergic differentiation and the evolution of the various dopaminergic systems are not well understood, as research has mostly focused on ascending mammalian dopaminergic systems of the substantia nigra and ventral tegmental area. Zebrafish have evolved as an excellent genetic and experimental embryological model to study specification and axonal projectivity of dopaminergic neurons. The large evolutionary distance between fish and mammals provides the opportunity to identify conserved core regulatory mechanisms that control differentiation and projection behavior of the various dopaminergic groups in vertebrates. Here, we present an overview of the formation of dopaminergic groups and their projections in zebrafish. We will further review the results from genetic analyses, which have revealed insights on signals as well as transcription factors contributing to dopaminergic differentiation. Together with recently established paradigms for behavioral analysis, dopaminergic systems are studied at all levels in zebrafish, from molecular and cellular to systems and behavioral.


Tyrosine Hydroxylase Dopaminergic Neuron Zebrafish Embryo Adult Zebrafish Larval Zebrafish 
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  1. 1.
    Kimmel CB, Ballard WW, Kimmel SR et al. Stages of embryonic development of the zebrafish. Dev Dyn 1995; 203(3):253–310.PubMedGoogle Scholar
  2. 2.
    Kuwada JY. Development of the zebrafish nervous system: Genetic analysis and manipulation. Curr Opin Neurobiol 1995; 5(1):50–4.CrossRefPubMedGoogle Scholar
  3. 3.
    Wen L, Wei W, Gu W et al. Visualization of monoaminergic neurons and neurotoxicity of MPTP in live transgenic zebrafish. Dev Biol 2008; 314(1):84–92.CrossRefPubMedGoogle Scholar
  4. 4.
    Kaslin J, Panula P. Comparative anatomy of the histaminergic and other aminergic systems in zebrafish (Danio rerio). J Comp Neurol 2001; 440(4):342–77.CrossRefPubMedGoogle Scholar
  5. 5.
    Ma PM. Catecholaminergic systems in the zebrafish. IV. Organization and projection pattern of dopaminergic neurons in the diencephalon. J Comp Neurol 2003; 460(1):13–37.CrossRefPubMedGoogle Scholar
  6. 6.
    Rink E, Wullimann MF. Development of the catecholaminergic system in the early zebrafish brain: an immunohistochemical study. Brain Res Dev Brain Res 2002; 137(1):89–100.CrossRefPubMedGoogle Scholar
  7. 7.
    Holzschuh J, Barrallo-Gimeno A, Ettl AK et al. Noradrenergic neurons in the zebrafish hindbrain are induced by retinoic acid and require tfap2a for expression of the neurotransmitter phenotype. Development 2003; 130(23):5741–54.CrossRefPubMedGoogle Scholar
  8. 8.
    Holzschuh J, Ryu S, Aberger F et al. Dopamine transporter expression distinguishes dopaminergic neurons from other catecholaminergic neurons in the developing zebrafish embryo. Mech Dev 2001; 101(1–2):237–43.CrossRefPubMedGoogle Scholar
  9. 9.
    Wullimann MF, Rupp B, Reichert H. Neuroanatomy of the zebrafish brain. Birkhaeuser Switzerland: Verlag, Basel, 1996.Google Scholar
  10. 10.
    Mueller T, Wullimann MF. Atlas of Early Zebrafish Brain Development. Amsterdam: Elsevier BV, 2005.Google Scholar
  11. 11.
    Puelles L, Verney C. Early neuromeric distribution of tyrosine-hydroxylase-immunoreactive neurons in human embryos. J Comp Neurol 1998; 394(3):283–308.CrossRefPubMedGoogle Scholar
  12. 12.
    Ryu S, Holzschuh J, Mahler J et al. Genetic analysis of dopaminergic system development in zebrafish. J Neural Trasm 2006; (70):61–6.CrossRefGoogle Scholar
  13. 13.
    Candy J, Collet C. Two tyrosine hydroxylase genes in teleosts. Biochim Biophys Acta 2005; 1727(1):35–44.PubMedGoogle Scholar
  14. 14.
    Smeets WJ, Marin O, Gonzalez A. Evolution of the basal ganglia: new perspectives through a comparative approach. J Anat 2000; 196(Pt 4):501–17.CrossRefPubMedGoogle Scholar
  15. 15.
    Rink E, Wullimann MF. The teleostean (zebrafish) dopaminergic system ascending to the subpallium (striatum) is located in the basal diencephalon (posterior tuberculum). Brain Res 2001; 889(1–2):316–30.CrossRefPubMedGoogle Scholar
  16. 16.
    Rink E, Wullimann MF. Connections of the ventral telencephalon and tyrosine hydroxylase distribution in the zebrafish brain (Danio rerio) lead to identification of an ascending dopaminergic system in a teleost. Brain Res Bull 2002; 57(3–4):385–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Pinuela C, Northcutt RG. Immunohistochemical organization of the forebrain in the white sturgeon, Acipenser transmontanus. Brain Behav Evol 2007; 69(4):229–53.CrossRefPubMedGoogle Scholar
  18. 18.
    Adolf B, Chapouton P, Lam CS et al. Conserved and acquired features of adult neurogenesis in the zebrafish telencephalon. Dev Biol 2006; 295(1):278–93.CrossRefPubMedGoogle Scholar
  19. 19.
    Chapouton P, Adolf B, Leucht C et al. her5 expression reveals a pool of neural stem cells in the adult zebrafish midbrain. Development 2006; 133(21):4293–303.CrossRefPubMedGoogle Scholar
  20. 20.
    Grandel H, Kaslin J, Ganz J et al. Neural stem cells and neurogenesis in the adult zebrafish brain: origin, proliferation dynamics, migration and cell fate. Dev Biol 2006; 295(1):263–77.CrossRefPubMedGoogle Scholar
  21. 21.
    McLean DL, Fetcho JR. Ontogeny and innervation patterns of dopaminergic, noradrenergic and serotonergic neurons in larval zebrafish. J Comp Neurol 2004; 480(1):38–56.CrossRefPubMedGoogle Scholar
  22. 22.
    Ma PM. Catecholaminergic systems in the zebrafish. II. Projection pathways and pattern of termination of the locus coeruleus. J Comp Neurol 1994; 344(2):256–69.CrossRefPubMedGoogle Scholar
  23. 23.
    Ma PM. Catecholaminergic systems in the zebrafish. III. Organization and projection pattern of medullary dopaminergic and noradrenergic neurons. J Comp Neurol 1997; 381(4):411–27.CrossRefPubMedGoogle Scholar
  24. 24.
    Guo S, Wilson SW, Cooke S et al. Mutations in the zebrafish unmask shared regulatory pathways controlling the development of catecholaminergic neurons. Dev Biol 1999; 208(2):473–87.CrossRefPubMedGoogle Scholar
  25. 25.
    Ye W, Shimamura K, Rubenstein JLR et al. FGF and Shh Signals Control Dopaminergic and Serotonergic Cell Fate in the Anterior Neural Plate. Cell 1998; 93:755–66.CrossRefPubMedGoogle Scholar
  26. 26.
    Holzschuh J, Hauptmann G, Driever W. Genetic analysis of the roles of Hh, FGF8 and nodal signaling during catecholaminergic system development in the zebrafish brain. J Neurosci 2003; 23(13):5507–19.PubMedGoogle Scholar
  27. 27.
    Del Giacco L, Sordino P, Pistocchi A et al. Differential regulation of the zebrafish orthopedia 1 gene during fate determination of diencephalic neurons. BMC Dev Biol 2006; 6:50.CrossRefPubMedGoogle Scholar
  28. 28.
    Rohr KB, Barth KA, Varga ZM et al. The nodal pathway acts upstream of hedgehog signaling to specify ventral telencephalic identity. Neuron 2001; 29(2):341–51.CrossRefPubMedGoogle Scholar
  29. 29.
    Mathieu J, Barth A, Rosa FM et al. Distinct and cooperative roles for Nodal and Hedgehog signals during hypothalamic development. Development 2002; 129(13):3055–65.PubMedGoogle Scholar
  30. 30.
    McCaffery P, Drager UC. High levels of a retinoic acid-generating dehydrogenase in the meso-telencephalic dopamine system. Proc Natl Acad Sci USA 1994; 91(16):7772–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Jacobs FM, Smits SM, Noorlander CW et al. Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3 deficiency. Development 2007; 134(14):2673–84.CrossRefPubMedGoogle Scholar
  32. 32.
    Smidt MP, Burbach JP. How to make a mesodiencephalic dopaminergic neuron. Nat Rev 2007; 8(1):21–32.CrossRefGoogle Scholar
  33. 33.
    Andrews GL, Yun K, Rubenstein JL et al. Dlx transcription factors regulate differentiation of dopaminergic neurons of the ventral thalamus. Mol Cell Neurosci 2003; 23(1):107–20.CrossRefPubMedGoogle Scholar
  34. 34.
    Ohyama K, Ellis P, Kimura S et al. Directed differentiation of neural cells to hypothalamic dopaminergic neurons. Development 2005; 132(23):5185–97.CrossRefPubMedGoogle Scholar
  35. 35.
    Filippi A, Durr K, Ryu S et al. Expression and function of nr4a2, lmx1b and pitx3 in zebrafish dopaminergic and noradrenergic neuronal development. BMC Dev Biol 2007; 7:135.CrossRefPubMedGoogle Scholar
  36. 36.
    Ryu S, Mahler J, Acampora D et al. Orthopedia homeodomain protein is essential for diencephalic dopaminergic neuron development. Curr Biol 2007; 17(10):873–80.CrossRefPubMedGoogle Scholar
  37. 37.
    Blechman J, Borodovsky N, Eisenberg M et al. Specification of hypothalamic neurons by dual regulation of the homeodomain protein Orthopedia. Development 2007; 134(24):4417–26.CrossRefPubMedGoogle Scholar
  38. 38.
    Levkowitz G, Zeller J, Sirotkin HI et al. Zinc finger protein too few controls the development of monoaminergic neurons. Nature Neurosci 2003; 6(1):28–33.CrossRefPubMedGoogle Scholar
  39. 39.
    Rink E, Guo S. The too few mutant selectively affects subgroups of monoaminergic neurons in the zebrafish forebrain. Neuroscience 2004; 127(1):147–54.CrossRefPubMedGoogle Scholar
  40. 40.
    Hirata T, Nakazawa M, Muraoka O et al. Zinc-finger genes Fez and Fez-like function in the establishment of diencephalon subdivisions. Development 2006; 133(20):3993–4004.CrossRefPubMedGoogle Scholar
  41. 41.
    Jeong JY, Einhorn Z, Mercurio S et al. Neurogenin1 is a determinant of zebrafish basal forebrain dopaminergic neurons and is regulated by the conserved zinc finger protein Tof/Fezl. Proc Natl Acad Sci USA 2006; 103(13):5143–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Anichtchik OV, Kaslin J, Peitsaro N et al. Neurochemical and behavioural changes in zebrafish Danio rerio after systemic administration of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 2004; 88(2):443–53.PubMedCrossRefGoogle Scholar
  43. 43.
    Bretaud S, Lee S, Guo S. Sensitivity of zebrafish to environmental toxins implicated in Parkinson’s disease. Neurotoxicol Teratol 2004; 26(6):857–64.CrossRefPubMedGoogle Scholar
  44. 44.
    Lam CS, Korzh V, Strahle U. Zebrafish embryos are susceptible to the dopaminergic neurotoxin MPTP. Eur J Neurosci 2005; 21(6):1758–62.CrossRefPubMedGoogle Scholar
  45. 45.
    McKinley ET, Baranowski TC, Blavo DO et al. Neuroprotection of MPTP-induced toxicity in zebrafish dopaminergic neurons. Brain Res Mol Brain Res 2005; 141(2):128–37.CrossRefPubMedGoogle Scholar
  46. 46.
    Parng C, Roy NM, Ton C et al. Neurotoxicity assessment using zebrafish. J Pharmacol Toxicol Methods. 2007; 55(1):103–12.CrossRefPubMedGoogle Scholar
  47. 47.
    Bretaud S, Li Q, Lockwood BL et al. A choice behavior for morphine reveals experience-dependent drug preference and underlying neural substrates in developing larval zebrafish. Neuroscience 2007; 146(3):1109–16.CrossRefPubMedGoogle Scholar
  48. 48.
    Cahill GM. Circadian melatonin rhythms in cultured zebrafish pineals are not affected by catecholamine receptor agonists. Gen Comp Endocrinol 1997; 105(2):270–5.CrossRefPubMedGoogle Scholar
  49. 49.
    Darland T, Dowling JE. Behavioral screening for cocaine sensitivity in mutagenized zebrafish. Proc Natl Acad Sci USA 2001; 98(20):11691–6.CrossRefPubMedGoogle Scholar
  50. 50.
    Lau B, Bretaud S, Huang Y et al. Dissociation of food and opiate preference by a genetic mutation in zebrafish. Genes Brain Behav 2006; 5(7):497–505.CrossRefPubMedGoogle Scholar
  51. 51.
    Boehmler W, Carr T, Thisse C et al. D4 Dopamine receptor genes of zebrafish and effects of the antipsychotic clozapine on larval swimming behaviour. Genes Brain Behav 2007; 6(2):155–66.CrossRefPubMedGoogle Scholar
  52. 52.
    Boehmler W Obrecht-Pflumio S, Canfield V et al. Evolution and expression of D2 and D3 dopamine receptor genes in zebrafish. Dev Dyn 2004; 230(3):481–93.CrossRefPubMedGoogle Scholar
  53. 53.
    Li P, Shah S, Huang L et al. Cloning and spatial and temporal expression of the zebrafish dopamine D1 receptor. Dev Dyn 2007; 236(5):1339–46.CrossRefPubMedGoogle Scholar
  54. 54.
    Burgess HA, Granato M. Modulation of locomotor activity in larval zebrafish during light adaptation. J Exp Biol 2007; 210(Pt 14):2526–39.CrossRefPubMedGoogle Scholar
  55. 55.
    Bally-Cuif L. Teleosts: simple organisms? Complex behavior. Zebrafish 2006; 3(2):127–30.CrossRefGoogle Scholar
  56. 56.
    Ninkovic J, Bally-Cuif L. The zebrafish as a model system for assessing the reinforcing properties of drugs of abuse. Methods San Diego: Calif, 2006; 39(3):262–74.Google Scholar
  57. 57.
    Ninkovic J, Folchert A, Makhankov YV et al. Genetic identification of AChE as a positive modulator of addiction to the psychostimulant D-amphetamine in zebrafish. J Neurobiol 2006; 66(5):463–75.CrossRefPubMedGoogle Scholar
  58. 58.
    Burgess HA, Granato M. Sensorimotor gating in larval zebrafish. J Neurosci 2007; 27(18):4984–94.CrossRefPubMedGoogle Scholar
  59. 59.
    Friedrich RW, Habermann CJ, Laurent G. Multiplexing using synchrony in the zebrafish olfactory bulb. Nature Neurosci 2004; 7(8):862–71.CrossRefPubMedGoogle Scholar
  60. 60.
    Meyer MP, Smith SJ. Evidence from in vivo imaging that synaptogenesis guides the growth and branching of axonal arbors by two distinct mechanisms. J Neurosci 2006; 26(13):3604–14.CrossRefPubMedGoogle Scholar
  61. 61.
    Zhang F, Wang LP, Brauner M et al. Multimodal fast optical interrogation of neural circuitry. Nature 2007; 446(7136):633–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Arenzana FJ, Arevalo R, Sanchez-Gonzalez R et al. Tyrosine hydroxylase immunoreactivity in the developing visual pathway of the zebrafish. Anat Embryol 2006; 211(4):323–34.CrossRefPubMedGoogle Scholar
  63. 63.
    Bjorklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci 2007; 30(5):194–202.CrossRefPubMedGoogle Scholar
  64. 64.
    Belting H-G, Hauptmann G, Meyer D et al spiel ohne grenzen/pou2 is required during establishment of the zebrafish midbrain-hindbrain boundary organizer. Development 2001; 128(21):4165–76.PubMedGoogle Scholar
  65. 65.
    Guo S, Yamaguchi Y, Schilbach S et al. A regulator of transcriptional elongation controls vertebrate neuronal development. Nature 2000; 408(6810):366–9.CrossRefPubMedGoogle Scholar
  66. 66.
    Durr K, Holzschuh J, Filippi A et al. Differential roles of transcriptional mediator complex subunits Crsp34/Med27, Crsp150/Med14 and Trap100/Med24 during zebrafish retinal development. Genetics 2006; 174(2):693–705.CrossRefPubMedGoogle Scholar
  67. 67.
    Wang X, Yang N, Uno E et al. A subunit of the mediator complex regulates vertebrate neuronal development. Proc Natl Acad Sci USA 2006; 103(46):17284–9.CrossRefPubMedGoogle Scholar
  68. 68.
    Lee SA, Shen EL, Fiser A et al. The zebrafish forkhead transcription factor Foxil specifies epibranchial placode-derived sensory neurons. Development 2003; 130(12):2669–79.CrossRefPubMedGoogle Scholar
  69. 69.
    Guo S, Brush J, Teraoka H et al. Development of noradrenergic neurons in the zebrafish hindbrain requires BMP, FGF8 and the homeodomain protein soulless/Phox2a. Neuron 1999; 24(3):555–66.CrossRefPubMedGoogle Scholar
  70. 70.
    Chen W, Burgess S, Hopkins N. Analysis of the zebrafish smoothened mutant reveals conserved and divergent functions of hedgehog activity. Development 2001; 128:2385–96.PubMedGoogle Scholar
  71. 71.
    Ryu S, Holzschuh J Erhardt S et al. Depletion of minichromosome maintenance protein 5 in the zebrafish retina causes cell-cycle defect and apoptosis. Proc Natl Acad Sci USA 2005; 102(51):18467–72.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Developmental Biology, Institute Biology 1, Faculty of BiologyUniversity of FreiburgFreiburgGermany

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