Advertisement

Terminal Differentiation of Mesodiencephalic Dopaminergic Neurons:

The Role of Nurr1 and Pitx3
  • Marten P. Smidt
  • J. Peter
  • H. Burbach
Part of the Advances in Experimental Medicine and Biology book series (volume 651)

Abstract

The orphan nuclear hormone receptor Nurr1 and the homeobox Pitx3 were the first two transcription factors that were implicated in the development of mesodiencephalic dopaminergic (mdDA) neurons.1,2 These factors have their own expression profile in the brain: Nurr1 is expressed in many forebrain regions, whereas Pitx3 is exclusively expressed in mdDA neurons. Functional analysis of the respective mouse mutants have emphasized the importance of both factors for mdDA development and their difference in mode of action: Nurr1 has been implicated particularly in specifying the dopaminergic neurotransmitter phenotype and in neuronal maintenance, while Pitx3 is essential for the development of a subset of mdDA neurons encompassing the SNc. Recent data on molecular mechanisms of action and regulation of target genes reveal a large complexity and suggest that Nurr1 and Pitx3 are part of extended regulatory networks. In this chapter we highlight the molecular programming of mdDA neurons3 4 from the viewpoint of Pitx3 and Nurr1.

Keywords

Dopaminergic Neuron Dopamine Neuron Orphan Nuclear Receptor Midbrain Dopaminergic Neuron MN9D Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Zetterström R, Solomin L, Jansson L et al. Dopamine neuron agenesis in Nurr1-deficient mice. Science 1997; 276(5310):248–250.CrossRefPubMedGoogle Scholar
  2. 2.
    Smidt M, vanSchaick H, Lanctôt C et al. A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc Natl Acad Sci USA 1997; 94(24):13305–10.CrossRefPubMedGoogle Scholar
  3. 3.
    Smits SM, Smidt MP. The role of Pitx3 in survival of midbrain dopaminergic neurons. J Neural Transm Suppl 2006; 70:57–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Smidt MP, Burbach JPH. How to make a mesodiencephalic dopaminergic neuron. Nat Rev Neurosci 2007; 8(1):21–32.CrossRefPubMedGoogle Scholar
  5. 5.
    Lamonerie T, Tremblay JJ, Lanctot C et al. Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene. Genes Dev 1996; 10(10):1284–95.CrossRefPubMedGoogle Scholar
  6. 6.
    Semina E, Reiter R, Leysens N et al. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in rieger syndrome. Nat Genet 1996; 14(4):392–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Gage PJ, Camper SA. Pituitary homeobox 2, a novel member of the bicoid-related family of homeobox genes, is a potential regulator of anterior structure formation. Hum Mol Genet 1997; 6(3):457–64.CrossRefPubMedGoogle Scholar
  8. 8.
    Smidt M, Cox J, vanSchaick H et al. Analysis of three Ptx2 splice variants on transcriptional activity and differential expression pattern in the brain. J Neurochem 2000; 75(5):1818–25.CrossRefPubMedGoogle Scholar
  9. 9.
    Semina EV, Reiter RS, Murray JC. Isolation of a new homeobox gene belonging to the pitx/rieg family: expression during lens development and mapping to the aphakia region on mouse chromosome 19. Hum Mol Genet 1997; 6(12):2109–2116.CrossRefPubMedGoogle Scholar
  10. 10.
    Varnum DS, Stevens LC. Aphakia, a new mutation in the mouse. J Hered 1968; 59(2):147–50.PubMedGoogle Scholar
  11. 11.
    Grimm C, Chatterjee B, Favor et al. Aphakia (ak), a mouse mutation affecting early eye development: fine mapping, consideration of candidate genes and altered pax6 and six3 gene expression pattern. Dev Genet 1998; 23(4):299–316.CrossRefPubMedGoogle Scholar
  12. 12.
    Graw J. Mouse models of congenital cataract. Eye 1998; 13(Pt 3b):438–44.Google Scholar
  13. 13.
    Graw J. Cataract mutations and lens development. Prog Retin Eye Res 1999; 18(2):235–67.CrossRefPubMedGoogle Scholar
  14. 14.
    Graw J, Loster J. Developmental genetics in ophthalmology. Ophthalmic Genet 2003; 24(1):1–33.CrossRefPubMedGoogle Scholar
  15. 15.
    Rieger DK, Reichenberger E, McLean W et al. A double-deletion mutation in the pitx3 gene causes arrested lens development in aphakia mice. Genomics 2001; 72(1):61–72.CrossRefPubMedGoogle Scholar
  16. 16.
    Smidt MP, Smits SM, Burbach JP. Molecular mechanisms underlying midbrain dopamine neuron development and function. Eur J Pharmacol 2003; 480(1–3):75–88.CrossRefPubMedGoogle Scholar
  17. 17.
    Smidt MP, Smits SM, Bouwmeester H et al. Early developmental failure of substantia nigra dopamine neurons in mice lacking the homeodomain gene pitx3. Development 2004; 131(5):1145–55.CrossRefPubMedGoogle Scholar
  18. 18.
    Semina EV, Ferrell RE, Mintz-Hittner HA et al. A novel homeobox gene pitx3 is mutated in families with autosomal-dominant cataracts and asmd. Nat Genet 1998; 19(2):167–170.CrossRefPubMedGoogle Scholar
  19. 19.
    Bidinost C, Matsumoto M, Chung D et al. Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities. Invest Ophthalmol Vis Sci 2006; 47(4):1274–1280.CrossRefPubMedGoogle Scholar
  20. 20.
    Smidt MP, Smits SM, Burbach JPH. Homeobox gene Pitx3 and its role in the development of dopamine neurons of the substantia nigra. Cell Tissue Res 2004; 318(1):35–43.CrossRefPubMedGoogle Scholar
  21. 21.
    L’Honoré A, Coulon V, Marcil A et al. Sequential expression and redundancy of pitx2 and pitx3 genes duringmuscle development. Dev Biol 2007; 307(2):421–433.CrossRefPubMedGoogle Scholar
  22. 22.
    Coulon V, L’Honoré A, Ouimette JF et al. A muscle-specific promoter directs pitx3 gene expression in skeletal muscle cells. J Biol Chem 2007; 282(45):33192–33200.CrossRefPubMedGoogle Scholar
  23. 23.
    Smidt MP, Asbreuk CH, Cox JJ et al. A second independent pathway for development of mesencephalic dopaminergic neurons requires lmx1b. Nat. Neurosci 2000; 3(4):337–41.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhao S, Maxwell S, Jimenez-Beristain A et al. Generation of embryonic stem cells and transgenic mice expressing green fluorescence protein in midbrain dopaminergic neurons. Eur J Neurosci 2004; 19(5):1133–40.CrossRefPubMedGoogle Scholar
  25. 25.
    Smidt M, Asbreuk C, Cox J et al. A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat Neurosci 2000; 3(4):337–41.CrossRefPubMedGoogle Scholar
  26. 26.
    Smidt MP, Smits SM, Bouwmeester H et al. Early developmental failure of substantia nigra dopamine neurons in mice lacking the homeodomain gene Pitx3. Development 2004; 131(5):1145–55.CrossRefPubMedGoogle Scholar
  27. 27.
    Cazorla P, Smidt M, O’Malley K et al. A response element for the homeodomain transcription factor Ptx3 in the tyrosine hydroxylase gene promoter. J Neurochem 2000; 74(5):1829–37.CrossRefPubMedGoogle Scholar
  28. 28.
    Lebel M, Gauthier Y, Moreau A et al. Pitx3 activates mouse tyrosine hydroxylase promoter via a high-affinity binding site. J Neurochem 2001; 77(2):558–67.CrossRefPubMedGoogle Scholar
  29. 29.
    Messmer K, Remington MP, Skidmore F et al. Induction of tyrosine hydroxylase expression by the transcription factor pitx3. Int J Dev Neurosci 2007; 25(1):29–37.CrossRefPubMedGoogle Scholar
  30. 30.
    Smits SM, Burbach JPH, Smidt MP. Developmental origin and fate of mesodiencephalic dopamine neurons. Prog Neurobiol 2006; 78(1):1–16.CrossRefPubMedGoogle Scholar
  31. 31.
    Jacobs FMJ, Smits SM, Noorlander CW et al. Retinoic acid counteracts developmental defects in the substantia nigra caused by pitx3 deficiency. Development 2007; 134(14):2673–2684.CrossRefPubMedGoogle Scholar
  32. 32.
    Burbach JPH, Smits S, Smidt MP. Transcription factors in the development of midbrain dopamine neurons. Ann N Y Acad Sci 2003; 991:61–8.PubMedGoogle Scholar
  33. 33.
    Smidt MP, Smits SM, Burbach JPH. Molecular mechanisms underlying midbrain dopamine neuron development and function. Eur J Pharmacol 2003; 480(1–3):75–88.CrossRefPubMedGoogle Scholar
  34. 34.
    Hwang DY, Ardayfio P, Kang UJ et al. Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice. Brain Res Mol Brain Res 2003; 114(2):123–31.CrossRefPubMedGoogle Scholar
  35. 35.
    van den Munckhof P, Luk KC, Ste-Marie L et al. Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons. Development 2003; 130(11):2535–42.CrossRefPubMedGoogle Scholar
  36. 36.
    Zhao S, Maxwell S, Jimenez-Beristain A et al. Generation of embryonic stem cells and transgenic mice expressing green fluorescence protein in midbrain dopaminergic neurons. Eur J Neurosci 2004; 19(5):1133–40.CrossRefPubMedGoogle Scholar
  37. 37.
    Maxwell SL, Ho HY, Kuehner E et al. Pitx3 regulates tyrosine hydroxylase expression in the substantia nigra and identifies a subgroup of mesencephalic dopaminergic progenitor neurons during mouse development. Dev Biol 2005; 282(2):467–79.CrossRefPubMedGoogle Scholar
  38. 38.
    Semina EV, Murray JC, Reiter R et al. Deletion in the promoter region and altered expression of pitx3 homeobox gene in aphakia mice. Hum Mol Genet 2000; 9(11):1575–1585.CrossRefPubMedGoogle Scholar
  39. 39.
    Rieger D, Reichenberger E, McLean W et al. A double-deletion mutation in the Pitx3 gene causes arrested lens development in aphakia mice. Genomics 2001; 72(1):61–72.CrossRefPubMedGoogle Scholar
  40. 40.
    Nunes I, Tovmasian LT, Silva RM et al. Pitx3 is required for development of substantia nigra dopaminergic neurons. Proc Natl Acad Sci USA 2003; 100(7):4245–50.CrossRefPubMedGoogle Scholar
  41. 41.
    Smits SM, Mathon DS, Burbach JPH et al. Molecular and cellular alterations in the Pitx3-deficient midbrain dopaminergic system. Mol Cell Neurosci 2005; 30(3):352–63.CrossRefPubMedGoogle Scholar
  42. 42.
    Teitelman G, Jaeger CB, Albert V et al. Expression of amino acid decarboxylase in proliferating cells of the neural tube and notochord of developing rat embryo. J Neurosci 1983; 3(7):1379–88.PubMedGoogle Scholar
  43. 43.
    Hynes M, Poulsen K, Tessier-Lavigne M et al. Control of neuronal diversity by the floor plate: contact-mediated induction of midbrain dopaminergic neurons. Cell 1995; 80(1):95–101.CrossRefPubMedGoogle Scholar
  44. 44.
    Davidson C, Ellinwood EH, Douglas SB et al. Effect of cocaine, nomifensine, gbr 12909 and win 35428 on carbon fiber microelectrode sensitivity for voltammetric recording of dopamine. J Neurosci Methods 2000; 101(1):75–83.CrossRefPubMedGoogle Scholar
  45. 45.
    Zhuang X, Oosting RS, Jones SR et al. Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci USA 2001; 98(4):1982–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Kas MJH, van der Linden AJA, Oppelaar H et al. Phenotypic segregation of aphakia and pitx3-null mutants reveals that pitx3 deficiency increases consolidation of specific movement components. Behav Brain Res 2008; 186(2):208–214.CrossRefPubMedGoogle Scholar
  47. 47.
    van den Munckhof P, Gilbert F, Chamberland M et al. Striatal neuroadaptation and rescue of locomotor deficit by l-dopa in aphakia mice, a model of parkinson’s disease. J Neurochem 2006; 96(1):160–170.CrossRefPubMedGoogle Scholar
  48. 48.
    Costall B, Naylor RJ, Nohria V. Climbing behaviour induced by apomorphine in mice: a potential model for the detection of neuroleptic activity. Eur J Pharmacol 1978; 50(1):39–50.CrossRefPubMedGoogle Scholar
  49. 49.
    Hwang DY, Fleming SM, Ardayfio P et al. 3,4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson’s disease. J Neurosci 2005; 25(8):2132–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Smits SM, Noorlander CW, Kas MJH et al. Alterations in serotonin signalling are involved in the hyperactivity of pitx3-deficient mice. Eur J Neurosci 2008; 27(2):388–395.PubMedCrossRefGoogle Scholar
  51. 51.
    Chung S, Hedlund E, Hwang M et al. The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons. Mol Cell Neurosci 2005; 28(2):241–52.CrossRefPubMedGoogle Scholar
  52. 52.
    Wallén A, Zetterström R, Solomin L et al. Fate of mesencephalic AHD2-expressing dopamine progenitor cells in NURR1 mutant mice. Exp Cell Res 1999; 253(2):737–46.CrossRefPubMedGoogle Scholar
  53. 53.
    Blentic A, Gale E, Maden M. Retinoic acid signalling centres in the avian embryo identified by sites of expression of synthesising and catabolising enzymes. Dev Dyn 2003; 227(1):114–127.CrossRefPubMedGoogle Scholar
  54. 54.
    Fan X, Molotkov A, Manabe SI et al. Targeted disruption of Aldh1a1 (Raldh1) provides evidence for a complex mechanism of retinoic acid synthesis in the developing retina. Mol Cell Biol 2003; 23(13):4637–4648.CrossRefPubMedGoogle Scholar
  55. 55.
    Molotkov A, Duester G. Genetic evidence that retinaldehyde dehydrogenase raldh1 (aldh1a1) functions downstream of alcohol dehydrogenase adh1 in metabolism of retinol to retinoic acid. J Biol Chem 2003; 278(38):36085–36090.CrossRefPubMedGoogle Scholar
  56. 56.
    Tasheva ES, Klocke B, Conrad GW. Analysis of transcriptional regulation of the small leucine rich proteoglycans. Mol Vis 2004; 10:758–72.PubMedGoogle Scholar
  57. 57.
    Peng C, Fan S, Li X et al. Overexpression of pitx3 upregulates expression of bdnf and gdnf in sh-sy5y cells and primary ventral mesencephalic cultures. FEBS Lett 2007; 581(7):1357–1361.CrossRefPubMedGoogle Scholar
  58. 58.
    Law S, Conneely O, DeMayo F et al. Identification of a new brain-specific transcription factor, NURR1. Mol Endocrinol 1992; 6(12):2129–35.CrossRefPubMedGoogle Scholar
  59. 59.
    Shiau AK, Coward P, Schwarz M et al. Orphan nuclear receptors: from new ligand discovery technologies to novel signaling pathways. Curr Opin Drug Discov Devel 2001; 4(5):575–590.PubMedGoogle Scholar
  60. 60.
    Michelhaugh SK, Vaitkevicius H, Wang J et al. Dopamine neurons express multiple isoforms of the nuclear receptor nurr1 with diminished transcriptional activity. J Neurochem 2005; 95(5):1342–1350.CrossRefPubMedGoogle Scholar
  61. 61.
    Ohkura N, Hosono T, Maruyama K et al. An isoform of nurr1 functions as a negative inhibitor of the ngfi-b family signaling. Biochim Biophys Acta 1999; 1444(1):69–79.PubMedGoogle Scholar
  62. 62.
    Saucedo-Cardenas O, Conneely OM. Comparative distribution of nurr1 and nur77 nuclear receptors in the mouse central nervous system. J Mol Neurosci 1996; 7(1):51–63.CrossRefPubMedGoogle Scholar
  63. 63.
    Xiao Q, Castillo S, Nikodem V. Distribution of messenger RNAs for the orphan nuclear receptors Nurr1 and Nur77 (NGFI-B) in adult rat brain using in situ hybridization. Neuroscience 1996; 75(1):221–30.CrossRefPubMedGoogle Scholar
  64. 64.
    Bäckman C, Perlmann T, Wallén A et al. A selective group of dopaminergic neurons express nurr1 in the adult mouse brain. Brain Res 1999; 851(1–2):125–132.CrossRefPubMedGoogle Scholar
  65. 65.
    Saucedo-Cardenas O, Quintana-Hau JD, Le WD et al. Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc Natl Acad Sci USA 1998; 95(7):4013–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Le W, Conneely O, Zou L et al. Selective agenesis of mesencephalic dopaminergic neurons in Nurr1-deficient mice. Exp Neurol 1999; 159(2):451–8.CrossRefPubMedGoogle Scholar
  67. 67.
    Smits SM, Ponnio T, Conneely OM et al. Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons. Eur Jneurosci 2003; 18(7):1731–8.CrossRefGoogle Scholar
  68. 68.
    A WA, Castro D, Zetterström R et al. Orphan nuclear receptor Nurr1 is essential for Ret expression in midbrain dopamine neurons and in the brain stem. Mol Cell Neurosci 2001; 18(6):649–63.CrossRefGoogle Scholar
  69. 69.
    Saucedo-Cardenas O, Quintana-Hau J, Le W et al. Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc Natl Acad Sci USA 1998; 95(7):4013–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Joseph B, Wallén-Mackenzie A, Benoit G et al. p57(Kip2) cooperates with Nurr1 in developing dopamine cells. Proc Natl Acad Sci USA 2003; 100(26):15619–24.CrossRefPubMedGoogle Scholar
  71. 71.
    Perlmann T, Jansson L. A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev 1995; 9(7):769–82.CrossRefPubMedGoogle Scholar
  72. 72.
    Aarnisalo P, Kim CH, Lee JW et al. Defining requirements for heterodimerization between the retinoid X receptor and the orphan nuclear receptor Nurr1. J Biol Chem 2002; 277(38):35118–23.CrossRefPubMedGoogle Scholar
  73. 73.
    Wallen-Mackenzie A, deUrquiza AM, Petersson S et al. Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells. Genes Dev 2003; 17(24):3036–47.CrossRefPubMedGoogle Scholar
  74. 74.
    deUrquiza AM, Liu S, Sjöberg M et al. Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 2000; 290(5499):2140–2144.CrossRefGoogle Scholar
  75. 75.
    Kitagawa H, Ray WJ, Glantschnig H et al. A regulatory circuit mediating convergence between nurr1 transcriptional regulation and wnt signaling. Mol Cell Biol 2007; 27(21):7486–7496.CrossRefPubMedGoogle Scholar
  76. 76.
    Sacchetti P, Carpentier R, Ségard P et al. Multiple signaling pathways regulate the transcriptional activity of the orphan nuclear receptor nurr1. Nucleic Acids Res 2006; 34(19):5515–5527.CrossRefPubMedGoogle Scholar
  77. 77.
    Gil M, McKinney C, Lee MK et al. Regulation of gtp cyclohydrolase i expression by orphan receptor nurr1 in cell culture and in vivo. J Neurochem 2007; 101(1):142–150.CrossRefPubMedGoogle Scholar
  78. 78.
    Jankovic J, Chen S, Le WD. The role of nurr1 in the development of dopaminergic neurons and parkinson’s disease. Prog Neurobiol 2005; 77(1–2):128–138.CrossRefPubMedGoogle Scholar
  79. 79.
    Hermanson E, Joseph B, Castro D et al. Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells. Exp Cell Res 2003; 288(2):324–34.CrossRefPubMedGoogle Scholar
  80. 80.
    Luo Y, Henricksen LA, Giuliano RE et al. Vip is a transcriptional target of nurr1 in dopaminergic cells. Exp Neurol 2007; 203(1):221–232.CrossRefPubMedGoogle Scholar
  81. 81.
    Volpicelli F, Caiazzo M, Greco D et al. Bdnf gene is a downstream target of nurr1 transcription factor in rat midbrain neurons in vitro. J Neurochem 2007; 102(2):441–453.CrossRefPubMedGoogle Scholar
  82. 82.
    Pirih FQ, Tang A, Ozkurt IC et al. Nuclear orphan receptor Nurr1 directly transactivates the osteocalcin gene in osteoblasts. J Biol Chem 2004; 279(51):53167–74.CrossRefPubMedGoogle Scholar
  83. 83.
    Bassett MH, Suzuki T, Sasano H et al. The orphan nuclear receptors NURR1 and NGFIB regulate adrenal aldosterone production. Mol Endocrinol 2004; 18(2):279–90.CrossRefPubMedGoogle Scholar
  84. 84.
    Hermanson E, Borgius L, Bergsland M et al. Neuropilin1 is a direct downstream target of Nurr1 in the developing brain stem. J Neurochem 2006; 97(5):1403–11.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and PharmacologyUniversity Medical Center UtrechtUtrecht

Personalised recommendations