Molecular mechanisms of dopaminergic subset specification: Fundamental aspects and clinical perspectives

Cellular and Molecular Life Sciences

Volumn 71, Issue 24, 2014, Pages 4703-4727

  Veenvliet, Jesse V ^a   Smidt, Marten P ^a  

^a UNIVERSITY OF AMSTERDAM   (Netherlands)

Author keywords

Development; Dopamine; En1; Midbrain; Neurodegeneration; Parkinson's disease; Pitx3; Subset specification; Substantia nigra; Transcription; Ventral tegmental area

Indexed keywords

TRANSCRIPTION FACTOR;

ANIMAL; BIOLOGICAL MODEL; CYTOLOGY; DOPAMINERGIC NERVE CELL; GENE EXPRESSION; GENE REGULATORY NETWORK; GENETICS; HUMAN; MESENCEPHALON; METABOLISM; SIGNAL TRANSDUCTION;

ANIMALS; DOPAMINERGIC NEURONS; GENE EXPRESSION; GENE REGULATORY NETWORKS; HUMANS; MESENCEPHALON; MODELS, GENETIC; MODELS, NEUROLOGICAL; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS;

EID: 84922481778     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-014-1681-5     Document Type: Review

References (220)

1. Hirsch E, Graybiel AM, Agid YA (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 334:345-348. doi: 10.1038/334345a0
2. Lees AJ, Hardy J, Revesz T (2009) Parkinson's disease. Lancet 373:2055-2066. doi: 10.1016/S0140-6736(09)60492-X
3. Smidt MP, Burbach JPH (2007) How to make a mesodiencephalic dopaminergic neuron. Nat Rev Neurosci 8:21-32. doi: 10.1038/nrn2039
4. Smits SM, Burbach JPH, Smidt MP (2006) Developmental origin and fate of meso-diencephalic dopamine neurons. Prog Neurobiol 78:1-16. doi: 10.1016/j.pneurobio.2005.12.003
5. Ang S-L (2009) Foxa1 and Foxa2 transcription factors regulate differentiation of midbrain dopaminergic neurons. Adv Exp Med Biol 651:58-65
6. Alves dos Santos MTM, Smidt MP (2011) En1 and Wnt signaling in midbrain dopaminergic neuronal development. Neural Dev 6:23. doi: 10.1186/1749-8104-6-23
7. Hegarty SV, Sullivan AM, O'Keeffe GW (2013) Midbrain dopaminergic neurons: a review of the molecular circuitry that regulates their development. Dev Biol 379:123-138. doi: 10.1016/j.ydbio.2013.04.014
8. Van den Heuvel DMA, Pasterkamp RJ (2008) Getting connected in the dopamine system. Prog Neurobiol 85:75-93. doi: 10.1016/j.pneurobio.2008.01.003
9. Hynes M, Rosenthal A (1999) Specification of dopaminergic and serotonergic neurons in the vertebrate CNS. Curr Opin Neurobiol 9:26-36
10. Wassarman KM, Lewandoski M, Campbell K et al (1997) Specification of the anterior hindbrain and establishment of a normal mid/hindbrain organizer is dependent on Gbx2 gene function. Development 124:2923-2934
11. Rhinn M, Brand M (2001) The midbrain-hindbrain boundary organizer. Curr Opin Neurobiol 11:34-42
12. Acampora D, Gulisano M, Broccoli V, Simeone A (2001) Otx genes in brain morphogenesis. Prog Neurobiol 64:69-95
13. Acampora D, Gulisano M, Simeone A (1999) Otx genes and the genetic control of brain morphogenesis. Mol Cell Neurosci 13:1-8. doi: 10.1006/mcne.1998.0730
14. Farkas LM, Dünker N, Roussa E et al (2003) Transforming growth factor-beta(s) are essential for the development of midbrain dopaminergic neurons in vitro and in vivo. J Neurosci 23:5178-5186
15. Roussa E, Krieglstein K (2004) Induction and specification of midbrain dopaminergic cells: focus on SHH, FGF8, and TGF-beta. Cell Tissue Res 318:23-33. doi: 10.1007/s00441-004-0916-4
16. Cai J, Schleidt S, Pelta-Heller J et al (2013) BMP and TGF-β pathway mediators are critical upstream regulators of Wnt signaling during midbrain dopamine differentiation in human pluripotent stem cells. Dev Biol 376:62-73. doi: 10.1016/j.ydbio.2013.01.012
17. Danielian PS, McMahon AP (1996) Engrailed-1 as a target of the Wnt-1 signalling pathway in vertebrate midbrain development. Nature 383:332-334. doi: 10.1038/383332a0
18. Castelo-Branco G, Wagner J, Rodriguez FJ et al (2003) Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. Proc Natl Acad Sci USA 100:12747-12752. doi: 10.1073/pnas.1534900100
19. Guo C, Qiu H-Y, Huang Y et al (2007) Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice. Development 134:317-325. doi: 10.1242/dev.02745
20. Wurst W, Prakash N (2014) Wnt1-regulated genetic networks in midbrain dopaminergic neuron development. J Mol Cell Biol 6:34-41. doi: 10.1093/jmcb/mjt046
21. Anderegg A, Lin H-P, Chen J-A et al (2013) An Lmx1b-miR135a2 regulatory circuit modulates Wnt1/Wnt signaling and determines the size of the midbrain dopaminergic progenitor pool. PLoS Genet 9:e1003973. doi: 10.1371/journal.pgen.1003973
22. Holder N, Hill J (1991) Retinoic acid modifies development of the midbrain-hindbrain border and affects cranial ganglion formation in zebrafish embryos. Development 113:1159-1170
23. Avantaggiato V, Acampora D, Tuorto F, Simeone A (1996) Retinoic acid induces stage-specific repatterning of the rostral central nervous system. Dev Biol 175:347-357. doi: 10.1006/dbio.1996.0120
24. Kele J, Simplicio N, Ferri ALM et al (2006) Neurogenin 2 is required for the development of ventral midbrain dopaminergic neurons. Development 133:495-505. doi: 10.1242/dev.02223
25. Tomita K, Moriyoshi K, Nakanishi S et al (2000) Mammalian achaete-scute and atonal homologs regulate neuronal versus glial fate determination in the central nervous system. EMBO J 19:5460-5472. doi: 10.1093/emboj/19.20.5460
26. Kim H-J, Sugimori M, Nakafuku M, Svendsen CN (2007) Control of neurogenesis and tyrosine hydroxylase expression in neural progenitor cells through bHLH proteins and Nurr1. Exp Neurol 203:394-405. doi: 10.1016/j.expneurol.2006.08.029
27. Puelles L, Rubenstein JLR (2003) Forebrain gene expression domains and the evolving prosomeric model. Trends Neurosci 26:469-476. doi: 10.1016/S0166-2236(03)00234-0
28. Rubenstein JL, Martinez S, Shimamura K, Puelles L (1994) The embryonic vertebrate forebrain: the prosomeric model. Science 266:578-580
29. Puelles L, Harrison M, Paxinos G, Watson C (2013) A developmental ontology for the mammalian brain based on the prosomeric model. Trends Neurosci 36:570-578. doi: 10.1016/j.tins.2013.06.004
30. Smits SM, Von Oerthel L, Hoekstra EJ et al (2013) Molecular marker differences relate to developmental position and subsets of mesodiencephalic dopaminergic neurons. PLoS ONE 8:e76037. doi: 10.1371/journal.pone.0076037
31. Doucet-Beaupré H, Lévesque M (2013) The role of developmental transcription factors in adult midbrain dopaminergic neurons. OA Neurosci 1(1):3
32. Smidt MP, Van Schaick HS, Lanctôt C et al (1997) A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc Natl Acad Sci USA 94:13305-13310
33. Smidt MP, Smits SM, Bouwmeester H et al (2004) Early developmental failure of substantia nigra dopamine neurons in mice lacking the homeodomain gene Pitx3. Development 131:1145-1155. doi: 10.1242/dev.01022
34. Rieger DK, Reichenberger E, McLean W et al (2001) A double-deletion mutation in the Pitx3 gene causes arrested lens development in aphakia mice. Genomics 72:61-72. doi: 10.1006/geno.2000.6464
35. Semina EV, Murray JC, Reiter R et al (2000) Deletion in the promoter region and altered expression of Pitx3 homeobox gene in aphakia mice. Hum Mol Genet 9:1575-1585
36. Hwang D-Y, Ardayfio P, Kang UJ et al (2003) Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice. Brain Res Mol Brain Res 114:123-131
37. Nunes I, Tovmasian LT, Silva RM et al (2003) Pitx3 is required for development of substantia nigra dopaminergic neurons. Proc Natl Acad Sci USA 100:4245-4250. doi: 10.1073/pnas.0230529100
38. Van den Munckhof P, Luk KC, Ste-Marie L et al (2003) Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons. Development 130:2535-2542
39. Maxwell SL, Ho H-Y, Kuehner E et al (2005) Pitx3 regulates tyrosine hydroxylase expression in the substantia nigra and identifies a subgroup of mesencephalic dopaminergic progenitor neurons during mouse development. Dev Biol 282:467-479. doi: 10.1016/j.ydbio.2005.03.028
40. Jacobs FMJ, Smits SM, Noorlander CW et al (2007) Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3 deficiency. Development 134:2673-2684. doi: 10.1242/dev.02865
41. Jacobs FMJ, Veenvliet JV, Almirza WH et al (2011) Retinoic acid-dependent and -independent gene-regulatory pathways of Pitx3 in meso-diencephalic dopaminergic neurons. Development 138:5213-5222. doi: 10.1242/dev.071704
42. McCaffery P, Dräger UC (1994) High levels of a retinoic acid-generating dehydrogenase in the meso-telencephalic dopamine system. PNAS 91:7772-7776
43. Peng C, Aron L, Klein R et al (2011) Pitx3 is a critical mediator of GDNF-induced BDNF expression in nigrostriatal dopaminergic neurons. J Neurosci 31:12802-12815. doi: 10.1523/JNEUROSCI.0898-11.2011
44. Kim J, Inoue K, Ishii J et al (2007) A MicroRNA feedback circuit in midbrain dopamine neurons. Science 317:1220-1224. doi: 10.1126/science.1140481
45. Heyer MP, Pani AK, Smeyne RJ et al (2012) Normal midbrain dopaminergic neuron development and function in miR-133b mutant mice. J Neurosci 32:10887-10894. doi: 10.1523/JNEUROSCI.1732-12.2012
46. Trajkovski M, Ahmed K, Esau CC, Stoffel M (2012) MyomiR-133 regulates brown fat differentiation through Prdm16. Nat Cell Biol 14:1330-1335. doi: 10.1038/ncb2612
47. Liu W, Bi P, Shan T et al (2013) miR-133a regulates adipocyte browning in vivo. PLoS Genet 9:e1003626. doi: 10.1371/journal.pgen.1003626
48. Volpicelli F, De Gregorio R, Pulcrano S et al (2012) Direct regulation of Pitx3 expression by Nurr1 in culture and in developing mouse midbrain. PLoS ONE 7:e30661. doi: 10.1371/journal.pone.0030661
49. Jacobs FMJ, Van der Linden AJA, Wang Y et al (2009) Identification of Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in meso-diencephalic dopamine neurons. Development 136:2363-2373. doi: 10.1242/dev.037556
50. Jacobs FMJ, Van Erp S, Van der Linden AJA et al (2009) Pitx3 potentiates Nurr1 in dopamine neuron terminal differentiation through release of SMRT-mediated repression. Development 136:531-540. doi: 10.1242/dev.029769
51. Chakrabarty K, Von Oerthel L, Hellemons A et al (2012) Genome wide expression profiling of the mesodiencephalic region identifies novel factors involved in early and late dopaminergic development. Biology Open. doi: 10.1242/bio.20121230
52. Martinat C, Bacci J-J, Leete T et al (2006) Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Proc Natl Acad Sci USA 103:2874-2879. doi: 10.1073/pnas.0511153103
53. Hwang D-Y, Hong S, Jeong J-W et al (2009) Vesicular monoamine transporter 2 and dopamine transporter are molecular targets of Pitx3 in the ventral midbrain dopamine neurons. J Neurochem 111:1202-1212. doi: 10.1111/j.1471-4159.2009.06404.x
54. Davis CA, Joyner AL (1988) Expression patterns of the homeo box-containing genes En-1 and En-2 and the proto-oncogene int-1 diverge during mouse development. Genes Dev 2:1736-1744
55. Nakamura H, Katahira T, Matsunaga E, Sato T (2005) Isthmus organizer for midbrain and hindbrain development. Brain Res Brain Res Rev 49:120-126. doi: 10.1016/j.brainresrev.2004.10.005
56. Albéri L, Sgadò P, Simon HH (2004) Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons. Development 131:3229-3236. doi: 10.1242/dev.01128
57. Simon HH, Thuret S, Alberi L (2004) Midbrain dopaminergic neurons: control of their cell fate by the engrailed transcription factors. Cell Tissue Res 318:53-61. doi: 10.1007/s00441-004-0973-8
58. Lahti L, Peltopuro P, Piepponen TP, Partanen J (2012) Cell-autonomous FGF signaling regulates anteroposterior patterning and neuronal differentiation in the mesodiencephalic dopaminergic progenitor domain. Development 139:894-905. doi: 10.1242/dev.071936
59. Wurst W, Auerbach AB, Joyner AL (1994) Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum. Development 120:2065-2075
60. Simon HH, Saueressig H, Wurst W et al (2001) Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J Neurosci 21:3126-3134
61. Sgadò P, Albéri L, Gherbassi D et al (2006) Slow progressive degeneration of nigral dopaminergic neurons in postnatal engrailed mutant mice. Proc Natl Acad Sci USA 103:15242-15247. doi: 10.1073/pnas.0602116103
62. Sonnier L, Le Pen G, Hartmann A et al (2007) Progressive loss of dopaminergic neurons in the ventral midbrain of adult mice heterozygote for engrailed 1. J Neurosci 27:1063-1071. doi: 10.1523/JNEUROSCI.4583-06.2007
63. Bilovocky NA, Romito-DiGiacomo RR, Murcia CL et al (2003) Factors in the genetic background suppress the engrailed-1 cerebellar phenotype. J Neurosci 23:5105-5112
64. Veenvliet JV, Dos Santos MTMA, Kouwenhoven WM et al (2013) Specification of dopaminergic subsets involves interplay of En1 and Pitx3. Development 140:3373-3384. doi: 10.1242/dev.094565
65. Bye CR, Thompson LH, Parish CL (2012) Birth dating of midbrain dopamine neurons identifies A9 enriched tissue for transplantation into Parkinsonian mice. Exp Neurol. doi: 10.1016/j.expneurol.2012.04.002
66. Chung CY, Seo H, Sonntag KC et al (2005) Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection. Hum Mol Genet 14:1709-1725. doi: 10.1093/hmg/ddi178
67. Rotzinger S, Vaccarino FJ (2003) Cholecystokinin receptor subtypes: role in the modulation of anxiety-related and reward-related behaviours in animal models. J Psychiatry Neurosci 28:171-181
68. Fitzmaurice AG, Rhodes SL, Lulla A et al (2013) Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. Proc Natl Acad Sci USA 110:636-641. doi: 10.1073/pnas.1220399110
69. Lane RF, Blaha CD, Phillips AG (1987) Cholecystokinin-induced inhibition of dopamine neurotransmission: comparison with chronic haloperidol treatment. Prog Neuropsychopharmacol Biol Psychiatry 11:291-299
70. Boyce S, Rupniak NM, Tye S et al (1990) Modulatory role for CCK-B antagonists in Parkinson's disease. Clin Neuropharmacol 13:339-347
71. Simeone A, Puelles E, Omodei D et al (2011) Otx genes in neurogenesis of mesencephalic dopaminergic neurons. Dev Neurobiol 71:665-679. doi: 10.1002/dneu.20877
72. Omodei D, Acampora D, Mancuso P et al (2008) Anterior-posterior graded response to Otx2 controls proliferation and differentiation of dopaminergic progenitors in the ventral mesencephalon. Development 135:3459-3470. doi: 10.1242/dev.027003
73. Di Giovannantonio LG, Di Salvio M, Acampora D et al (2013) Otx2 selectively controls the neurogenesis of specific neuronal subtypes of the ventral tegmental area and compensates En1-dependent neuronal loss and MPTP vulnerability. Dev Biol 373:176-183. doi: 10.1016/j.ydbio.2012.10.022
74. Di Salvio M, Di Giovannantonio LG, Acampora D et al (2010) Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP. Nat Neurosci 13:1481-1488. doi: 10.1038/nn.2661
75. Di Salvio M, Di Giovannantonio LG, Omodei D et al (2010) Otx2 expression is restricted to dopaminergic neurons of the ventral tegmental area in the adult brain. Int J Dev Biol 54:939-945. doi: 10.1387/ijdb.092974ms
76. Chung CY, Licznerski P, Alavian KN et al (2010) The transcription factor orthodenticle homeobox 2 influences axonal projections and vulnerability of midbrain dopaminergic neurons. Brain 133:2022-2031. doi: 10.1093/brain/awq142
77. Tripathi PP, Di Giovannantonio LG, Sanguinetti E et al (2014) Increased dopaminergic innervation in the brain of conditional mutant mice overexpressing Otx2: effects on locomotor behavior and seizure susceptibility. Neuroscience 261:173-183. doi: 10.1016/j.neuroscience.2013.12.045
78. Kim RH, Smith PD, Aleyasin H et al (2005) Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci USA 102:5215-5220. doi: 10.1073/pnas.0501282102
79. Smith PD, Crocker SJ, Jackson-Lewis V et al (2003) Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci USA 100:13650-13655. doi: 10.1073/pnas.2232515100
80. Wang S, Hu L-F, Yang Y et al (2005) Studies of ATP-sensitive potassium channels on 6-hydroxydopamine and haloperidol rat models of Parkinson's disease: implications for treating Parkinson's disease? Neuropharmacology 48:984-992. doi: 10.1016/j.neuropharm.2005.01.009
81. Pifl C, Giros B, Caron MG (1993) Dopamine transporter expression confers cytotoxicity to low doses of the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium. J Neurosci 13:4246-4253
82. Bezard E, Gross CE, Fournier MC et al (1999) Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter. Exp Neurol 155:268-273. doi: 10.1006/exnr.1998.6995
83. Andersson E, Tryggvason U, Deng Q et al (2006) Identification of intrinsic determinants of midbrain dopamine neurons. Cell 124:393-405. doi: 10.1016/j.cell.2005.10.037
84. Chung S, Leung A, Han B-S et al (2009) Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHH-FoxA2 pathway. Cell Stem Cell 5:646-658. doi: 10.1016/j.stem.2009.09.015
85. Yan CH, Levesque M, Claxton S et al (2011) Lmx1a and lmx1b function cooperatively to regulate proliferation, specification, and differentiation of midbrain dopaminergic progenitors. J Neurosci 31:12413-12425. doi: 10.1523/JNEUROSCI.1077-11.2011
86. Hoekstra EJ, Von Oerthel L, Van der Heide LP et al (2013) Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/B-catenin signaling activator R-spondin 2. PLoS ONE 8:e74049. doi: 10.1371/journal.pone.0074049
87. Deng Q, Andersson E, Hedlund E et al (2011) Specific and integrated roles of Lmx1a, Lmx1b and Phox2a in ventral midbrain development. Development 138:3399-3408. doi: 10.1242/dev.065482
88. Ono Y, Nakatani T, Sakamoto Y et al (2007) Differences in neurogenic potential in floor plate cells along an anteroposterior location: midbrain dopaminergic neurons originate from mesencephalic floor plate cells. Development 134:3213-3225. doi: 10.1242/dev.02879
89. Smidt MP, Asbreuk CH, Cox JJ et al (2000) A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat Neurosci 3:337-341. doi: 10.1038/73902
90. Adams KA, Maida JM, Golden JA, Riddle RD (2000) The transcription factor Lmx1b maintains Wnt1 expression within the isthmic organizer. Development 127:1857-1867
91. Smits SM, Ponnio T, Conneely OM et al (2003) Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons. Eur J Neurosci 18:1731-1738
92. Zetterström RH, Solomin L, Jansson L et al (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248-250
93. Saucedo-Cardenas O, Quintana-Hau JD, Le WD et al (1998) 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 95:4013-4018
94. Kadkhodaei B, Ito T, Joodmardi E et al (2009) Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci 29:15923-15932. doi: 10.1523/JNEUROSCI.3910-09.2009
95. Kadkhodaei B, Alvarsson A, Schintu N et al (2013) Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons. Proc Natl Acad Sci USA 110:2360-2365. doi: 10.1073/pnas.1221077110
96. Van Heesbeen HJ, Mesman S, Veenvliet JV, Smidt MP (2013) Epigenetic mechanisms in the development and maintenance of dopaminergic neurons. Development 140:1159-1169. doi: 10.1242/dev.089359
97. Stott SRW, Metzakopian E, Lin W et al (2013) Foxa1 and foxa2 are required for the maintenance of dopaminergic properties in ventral midbrain neurons at late embryonic stages. J Neurosci 33:8022-8034. doi: 10.1523/JNEUROSCI.4774-12.2013
98. Metzakopian E, Lin W, Salmon-Divon M et al (2012) Genome-wide characterization of Foxa2 targets reveals upregulation of floor plate genes and repression of ventrolateral genes in midbrain dopaminergic progenitors. Development 139:2625-2634. doi: 10.1242/dev.081034
99. Ferri ALM, Lin W, Mavromatakis YE et al (2007) Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development 134:2761-2769. doi: 10.1242/dev.000141
100. Lin W, Metzakopian E, Mavromatakis YE et al (2009) Foxa1 and Foxa2 function both upstream of and cooperatively with Lmx1a and Lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development. Dev Biol 333:386-396. doi: 10.1016/j.ydbio.2009.07.006
101. Kittappa R, Chang WW, Awatramani RB, McKay RDG (2007) The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age. PLoS Biol 5:e325. doi: 10.1371/journal.pbio.0050325
102. Hanks M, Wurst W, Anson-Cartwright L et al (1995) Rescue of the En-1 mutant phenotype by replacement of En-1 with En-2. Science 269:679-682
103. Sgadò P, Viaggi C, Pinna A et al (2011) Behavioral, neurochemical, and electrophysiological changes in an early spontaneous mouse model of nigrostriatal degeneration. Neurotox Res 20:170-181. doi: 10.1007/s12640-010-9232-9
104. Andressoo J-O, Saarma M (2008) Signalling mechanisms underlying development and maintenance of dopamine neurons. Curr Opin Neurobiol 18:297-306. doi: 10.1016/j.conb.2008.07.005
105. Joksimovic M, Awatramani R (2014) Wnt/β-catenin signaling in midbrain dopaminergic neuron specification and neurogenesis. J Mol Cell Biol 6:27-33. doi: 10.1093/jmcb/mjt043
106. Kipp M, Karakaya S, Pawlak J et al (2006) Estrogen and the development and protection of nigrostriatal dopaminergic neurons: concerted action of a multitude of signals, protective molecules, and growth factors. Front Neuroendocrinol 27:376-390. doi: 10.1016/j.yfrne.2006.07.001
107. Aron L, Klein R (2011) Repairing the parkinsonian brain with neurotrophic factors. Trends Neurosci 34:88-100. doi: 10.1016/j.tins.2010.11.001
108. Howells DW, Porritt MJ, Wong JY et al (2000) Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra. Exp Neurol 166:127-135. doi: 10.1006/exnr.2000.7483
109. Peng C, Fan S, Li X et al (2007) Overexpression of pitx3 upregulates expression of BDNF and GDNF in SH-SY5Y cells and primary ventral mesencephalic cultures. FEBS Lett 581:1357-1361. doi: 10.1016/j.febslet.2007.02.054
110. Yang D, Peng C, Li X et al (2008) Pitx3-transfected astrocytes secrete brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor and protect dopamine neurons in mesencephalon cultures. J Neurosci Res 86:3393-3400. doi: 10.1002/jnr.21774
111. Yu L, Saarma M, Arumäe U (2008) Death receptors and caspases but not mitochondria are activated in the GDNF- or BDNF-deprived dopaminergic neurons. J Neurosci 28:7467-7475. doi: 10.1523/JNEUROSCI.1877-08.2008
112. Clark J, Silvaggi JM, Kiselak T et al (2012) Pgc-1α overexpression downregulates Pitx3 and increases susceptibility to MPTP toxicity associated with decreased Bdnf. PLoS ONE 7:e48925. doi: 10.1371/journal.pone.0048925
113. St-Pierre J, Drori S, Uldry M et al (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397-408. doi: 10.1016/j.cell.2006.09.024
114. Zheng B, Liao Z, Locascio JJ et al (2010) PGC-1?, a potential therapeutic target for early intervention in Parkinson's disease. Sci Transl Med 2:52ra73. doi: 10.1126/scitranslmed.3001059
115. Kramer ER, Aron L, Ramakers GMJ et al (2007) Absence of Ret signaling in mice causes progressive and late degeneration of the nigrostriatal system. PLoS Biol 5:e39. doi: 10.1371/journal.pbio.0050039
116. Pascual A, Hidalgo-Figueroa M, Piruat JI et al (2008) Absolute requirement of GDNF for adult catecholaminergic neuron survival. Nat Neurosci 11:755-761. doi: 10.1038/nn.2136
117. Blum M (1998) A null mutation in TGF-alpha leads to a reduction in midbrain dopaminergic neurons in the substantia nigra. Nat Neurosci 1:374-377. doi: 10.1038/1584
118. Moqrich A, Earley TJ, Watson J et al (2004) Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate. Nat Neurosci 7:812-818. doi: 10.1038/nn1283
119. Bourane S, Garces A, Venteo S et al (2009) Low-threshold mechanoreceptor subtypes selectively express MafA and are specified by Ret signaling. Neuron 64:857-870. doi: 10.1016/j.neuron.2009.12.004
120. Partanen J (2007) FGF signalling pathways in development of the midbrain and anterior hindbrain. J Neurochem 101:1185-1193. doi: 10.1111/j.1471-4159.2007.04463.x
121. Shtutman M, Zhurinsky J, Simcha I et al (1999) The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 96:5522-5527
122. Ratzka A, Baron O, Stachowiak MK, Grothe C (2012) Fibroblast growth factor 2 regulates dopaminergic neuron development in vivo. J Neurochem 122:94-105. doi: 10.1111/j.1471-4159.2012.07768.x
123. Timmer M, Cesnulevicius K, Winkler C et al (2007) Fibroblast growth factor (FGF)-2 and FGF receptor 3 are required for the development of the substantia nigra, and FGF-2 plays a crucial role for the rescue of dopaminergic neurons after 6-hydroxydopamine lesion. J Neurosci 27:459-471. doi: 10.1523/JNEUROSCI.4493-06.2007
124. Baron O, Ratzka A, Grothe C (2012) Fibroblast growth factor 2 regulates adequate nigrostriatal pathway formation in mice. J Comp Neurol 520:3949-3961. doi: 10.1002/cne.23138
125. Blak AA, Naserke T, Saarimäki-Vire J et al (2007) Fgfr2 and Fgfr3 are not required for patterning and maintenance of the midbrain and anterior hindbrain. Developmental Biology 303:231-243. doi: 10.1016/j.ydbio.2006.11.008
126. Trokovic R, Trokovic N, Hernesniemi S et al (2003) FGFR1 is independently required in both developing mid- and hindbrain for sustained response to isthmic signals. EMBO J 22:1811-1823. doi: 10.1093/emboj/cdg169
127. Jukkola T, Lahti L, Naserke T et al (2006) FGF regulated gene-expression and neuronal differentiation in the developing midbrain-hindbrain region. Dev Biol 297:141-157. doi: 10.1016/j.ydbio.2006.05.002
128. Saarimäki-Vire J, Peltopuro P, Lahti L et al (2007) Fibroblast growth factor receptors cooperate to regulate neural progenitor properties in the developing midbrain and hindbrain. J Neurosci 27:8581-8592. doi: 10.1523/JNEUROSCI.0192-07.2007
129. Klejbor I, Myers JM, Hausknecht K et al (2006) Fibroblast growth factor receptor signaling affects development and function of dopamine neurons-inhibition results in a schizophrenia-like syndrome in transgenic mice. J Neurochem 97:1243-1258. doi: 10.1111/j.1471-4159.2006.03754.x
130. Itoh N, Ohta H (2013) Roles of FGF20 in dopaminergic neurons and Parkinson's disease. Front Mol Neurosci 6:15. doi: 10.3389/fnmol.2013.00015
131. Murase S, McKay RD (2006) A specific survival response in dopamine neurons at most risk in Parkinson's disease. J Neurosci 26:9750-9760. doi: 10.1523/JNEUROSCI.2745-06.2006
132. Wallén A, Zetterström RH, Solomin L et al (1999) Fate of mesencephalic AHD2-expressing dopamine progenitor cells in NURR1 mutant mice. Exp Cell Res 253:737-746. doi: 10.1006/excr.1999.4691
133. Chung S, Hedlund E, Hwang M et al (2005) The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons. Mol Cell Neurosci 28:241-252. doi: 10.1016/j.mcn.2004.09.008
134. De Urquiza AM, Liu S, Sjöberg M et al (2000) Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290:2140-2144
135. Papanikolaou T, Amano T, Lennington J et al (2009) In-vitro analysis of Pitx3 in mesodiencephalic dopaminergic neuron maturation. Eur J Neurosci 29:2264-2275. doi: 10.1111/j.1460-9568.2009.06784.x
136. Castro DS, Hermanson E, Joseph B et al (2001) Induction of cell cycle arrest and morphological differentiation by Nurr1 and retinoids in dopamine MN9D cells. J Biol Chem 276:43277-43284. doi: 10.1074/jbc.M107013200
137. Chang Y-L, Chen S-J, Kao C-L et al (2012) Docosahexaenoic acid promotes dopaminergic differentiation in induced pluripotent stem cells and inhibits teratoma formation in rats with Parkinson-like pathology. Cell Transplant 21:313-332. doi: 10.3727/096368911X580572
138. Jeong H, Kim M-S, Kim S-W et al (2006) Regulation of tyrosine hydroxylase gene expression by retinoic acid receptor. J Neurochem 98:386-394. doi: 10.1111/j.1471-4159.2006.03866.x
139. Katsuki H, Kurimoto E, Takemori S et al (2009) Retinoic acid receptor stimulation protects midbrain dopaminergic neurons from inflammatory degeneration via BDNF-mediated signaling. J Neurochem 110:707-718. doi: 10.1111/j.1471-4159.2009.06171.x
140. Schilling TF, Nie Q, Lander AD (2012) Dynamics and precision in retinoic acid morphogen gradients. Curr Opin Genet Dev 22:562-569. doi: 10.1016/j.gde.2012.11.012
141. Zhang L, Radtke K, Zheng L et al (2012) Noise drives sharpening of gene expression boundaries in the zebrafish hindbrain. Mol Syst Biol 8:613. doi: 10.1038/msb.2012.45
142. Qin P, Haberbusch JM, Soprano KJ, Soprano DR (2004) Retinoic acid regulates the expression of PBX1, PBX2, and PBX3 in P19 cells both transcriptionally and post-translationally. J Cell Biochem 92:147-163. doi: 10.1002/jcb.20057
143. Vitobello A, Ferretti E, Lampe X et al (2011) Hox and Pbx factors control retinoic acid synthesis during hindbrain Segmentation. Dev Cell 20:469-482. doi: 10.1016/j.devcel.2011.03.011
144. Kam RKT, Shi W, Chan SO et al (2013) Dhrs3 protein attenuates retinoic acid signaling and is required for early embryonic patterning. J Biol Chem 288:31477-31487. doi: 10.1074/jbc.M113.514984
145. White RJ, Nie Q, Lander AD, Schilling TF (2007) Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biol 5:e304. doi: 10.1371/journal.pbio.0050304
146. Topletz AR, Thatcher JE, Zelter A et al (2012) Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases. Biochem Pharmacol 83:149-163. doi: 10.1016/j.bcp.2011.10.007
147. Galter D, Buervenich S, Carmine A et al (2003) ALDH1 mRNA: presence in human dopamine neurons and decreases in substantia nigra in Parkinson's disease and in the ventral tegmental area in schizophrenia. Neurobiol Dis 14:637-647. doi: 10.1016/j.nbd.2003.09.001
148. Bossers K, Meerhoff G, Balesar R et al (2009) Analysis of gene expression in Parkinson's disease: possible involvement of neurotrophic support and axon guidance in dopaminergic cell death. Brain Pathol 19:91-107. doi: 10.1111/j.1750-3639.2008.00171.x
149. Moran LB, Duke DC, Deprez M et al (2006) Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson's disease. Neurogenetics 7:1-11. doi: 10.1007/s10048-005-0020-2
150. Kurauchi Y, Hisatsune A, Isohama Y et al (2011) Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF. J Neurochem 116:323-333. doi: 10.1111/j.1471-4159.2010.06916.x
151. Moon YS, Smas CM, Lee K et al (2002) Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Mol Cell Biol 22:5585-5592
152. Abdallah BM, Jensen CH, Gutierrez G et al (2004) Regulation of human skeletal stem cells differentiation by Dlk1/Pref-1. J Bone Miner Res 19:841-852. doi: 10.1359/JBMR.040118
153. Enomoto H, Furuichi T, Zanma A et al (2004) Runx2 deficiency in chondrocytes causes adipogenic changes in vitro. J Cell Sci 117:417-425. doi: 10.1242/jcs.00866
154. Hansen LH, Madsen B, Teisner B et al (1998) Characterization of the inhibitory effect of growth hormone on primary preadipocyte differentiation. Mol Endocrinol 12:1140-1149
155. Smas CM, Chen L, Zhao L et al (1999) Transcriptional repression of pref-1 by glucocorticoids promotes 3T3-L1 adipocyte differentiation. J Biol Chem 274:12632-12641
156. Christophersen NS, Grønborg M, Petersen TN et al (2007) Midbrain expression of Delta-like 1 homologue is regulated by GDNF and is associated with dopaminergic differentiation. Exp Neurol 204:791-801. doi: 10.1016/j.expneurol.2007.01.014
157. Jensen CH, Meyer M, Schroder HD et al (2001) Neurons in the monoaminergic nuclei of the rat and human central nervous system express FA1/dlk. NeuroReport 12:3959-3963
158. Bauer M, Szulc J, Meyer M et al (2008) Delta-like 1 participates in the specification of ventral midbrain progenitor derived dopaminergic neurons. J Neurochem 104:1101-1115. doi: 10.1111/j.1471-4159.2007.05037.x
159. Kim Y (2010) Effect of retinoic acid and delta-like 1 homologue (DLK1) on differentiation in neuroblastoma. Nutr Res Pract 4:276-282. doi: 10.4162/nrp.2010.4.4.276
160. Armengol J, Villena JA, Hondares E et al (2012) Pref-1 in brown adipose tissue: specific involvement in brown adipocyte differentiation and regulatory role of C/EBPδ. Biochem J. doi: 10.1042/BJ20111714
161. Hudak CS, Sul HS (2013) Pref-1, a gatekeeper of adipogenesis. Front Endocrinol (Lausanne) 4:79. doi: 10.3389/fendo.2013.00079
162. Müller D, Cherukuri P, Henningfeld K et al (2014) Dlk1 promotes a fast motor neuron biophysical signature required for peak force execution. Science 343:1264-1266. doi: 10.1126/science.1246448
163. Raghunandan R, Ruiz-Hidalgo M, Jia Y et al (2008) Dlk1 influences differentiation and function of B lymphocytes. Stem Cells Dev 17:495-507. doi: 10.1089/scd.2007.0102
164. Wheeler SR, Stagg SB, Crews ST (2008) Multiple Notch signaling events control drosophila CNS midline neurogenesis, gliogenesis and neuronal identity. Development 135:3071-3079. doi: 10.1242/dev.022343
165. Tio M, Toh J, Fang W et al (2011) Asymmetric cell division and notch signaling specify dopaminergic neurons in drosophila. PLoS ONE 6:e26879. doi: 10.1371/journal.pone.0026879
166. Falix FA, Aronson DC, Lamers WH, Gaemers IC (2012) Possible roles of DLK1 in the Notch pathway during development and disease. Biochim Biophys Acta. doi: 10.1016/j.bbadis.2012.02.003
167. Haubenberger D, Reinthaler E, Mueller JC et al (2011) Association of transcription factor polymorphisms PITX3 and EN1 with Parkinson's disease. Neurobiol Aging 32:302-307. doi: 10.1016/j.neurobiolaging.2009.02.015
168. Bergman O, Håkansson A, Westberg L et al (2010) PITX3 polymorphism is associated with early onset Parkinson's disease. Neurobiol Aging 31:114-117. doi: 10.1016/j.neurobiolaging.2008.03.008
169. Fuchs J, Mueller JC, Lichtner P et al (2009) The transcription factor PITX3 is associated with sporadic Parkinson's disease. Neurobiol Aging 30:731-738. doi: 10.1016/j.neurobiolaging.2007.08.014
170. Zheng K, Heydari B, Simon DK (2003) A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease. Arch Neurol 60:722-725. doi: 10.1001/archneur.60.5.722
171. Bergman O, Håkansson A, Westberg L et al (2009) Do polymorphisms in transcription factors LMX1A and LMX1B influence the risk for Parkinson's disease? J Neural Transm 116:333-338. doi: 10.1007/s00702-009-0187-z
172. Grünblatt E, Zehetmayer S, Jacob CP et al (2010) Pilot study: peripheral biomarkers for diagnosing sporadic Parkinson's disease. J Neural Transm 117:1387-1393. doi: 10.1007/s00702-010-0509-1
173. Karamohamed S, Latourelle JC, Racette BA et al (2005) BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study. Neurology 65:1823-1825. doi: 10.1212/01.wnl.0000187075.81589.fd
174. Pihlstrøm L, Axelsson G, Bjørnarå KA et al (2013) Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease. Neurobiol Aging 34(1708):e7-e13. doi: 10.1016/j.neurobiolaging.2012.10.019
175. Goris A, Williams-Gray CH, Foltynie T et al (2007) Investigation of TGFB2 as a candidate gene in multiple sclerosis and Parkinson's disease. J Neurol 254:846-848. doi: 10.1007/s00415-006-0414-6
176. Sulzer D (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson's disease. Trends Neurosci 30:244-250. doi: 10.1016/j.tins.2007.03.009
177. Alvarez-Fischer D, Fuchs J, Castagner F et al (2011) Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults. Nat Neurosci 14:1260-1266. doi: 10.1038/nn.2916
178. L'honoré A, Commère P-H, Ouimette J-F et al (2014) Redox regulation by pitx2 and pitx3 is critical for fetal myogenesis. Dev Cell 29:392-405. doi: 10.1016/j.devcel.2014.04.006
179. Spatazza J, Di Lullo E, Joliot A et al (2013) Homeoprotein signaling in development, health, and disease: a shaking of dogmas offers challenges and promises from bench to bed. Pharmacol Rev 65:90-104. doi: 10.1124/pr.112.006577
180. Chan CS, Guzman JN, Ilijic E et al (2007) "Rejuvenation" protects neurons in mouse models of Parkinson's disease. Nature 447:1081-1086. doi: 10.1038/nature05865
181. Khaliq ZM, Bean BP (2010) Pacemaking in dopaminergic ventral tegmental area neurons: depolarizing drive from background and voltage-dependent sodium conductances. J Neurosci 30:7401-7413. doi: 10.1523/JNEUROSCI.0143-10.2010
182. Chan CS, Gertler TS, Surmeier DJ (2009) Calcium homeostasis, selective vulnerability and Parkinson's disease. Trends Neurosci 32:249-256. doi: 10.1016/j.tins.2009.01.006
183. Mosharov EV, Larsen KE, Kanter E et al (2009) Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 62:218-229. doi: 10.1016/j.neuron.2009.01.033
184. Yamada T, McGeer PL, Baimbridge KG, McGeer EG (1990) Relative sparing in Parkinson's disease of substantia nigra dopamine neurons containing calbindin-D28 K. Brain Res 526:303-307
185. Liss B, Haeckel O, Wildmann J et al (2005) K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat Neurosci 8:1742-1751. doi: 10.1038/nn1570
186. Arenas E (2010) Towards stem cell replacement therapies for Parkinson's disease. Biochem Biophys Res Commun 396:152-156. doi: 10.1016/j.bbrc.2010.04.037
187. Gaillard A, Jaber M (2011) Rewiring the brain with cell transplantation in Parkinson's disease. Trends Neurosci 34:124-133. doi: 10.1016/j.tins.2011.01.003
188. Toulouse A, Sullivan AM (2008) Progress in Parkinson's disease-where do we stand? Prog Neurobiol 85:376-392. doi: 10.1016/j.pneurobio.2008.05.003
189. Kriks S, Shim J-W, Piao J et al (2011) Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480:547-551. doi: 10.1038/nature10648
190. Ganat YM, Calder EL, Kriks S et al (2012) Identification of embryonic stem cell-derived midbrain dopaminergic neurons for engraftment. J Clin Invest 122:2928-2939. doi: 10.1172/JCI58767
191. Caiazzo M, Dell'Anno MT, Dvoretskova E et al (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476:224-227. doi: 10.1038/nature10284
192. Wernig M, Zhao J-P, Pruszak J et al (2008) Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci USA 105:5856-5861. doi: 10.1073/pnas.0801677105
193. Hedlund E, Pruszak J, Lardaro T et al (2008) Embryonic stem cell-derived Pitx3-enhanced green fluorescent protein midbrain dopamine neurons survive enrichment by fluorescence-activated cell sorting and function in an animal model of Parkinson's disease. Stem Cells 26:1526-1536. doi: 10.1634/stemcells.2007-0996
194. Salti A, Nat R, Neto S et al (2013) Expression of early developmental markers predicts the efficiency of embryonic stem cell differentiation into midbrain dopaminergic neurons. Stem Cells Dev 22:397-411. doi: 10.1089/scd.2012.0238
195. Hwang D-Y, Kim D-S, Kim D-W (2010) Human ES and iPS cells as cell sources for the treatment of Parkinson's disease: current state and problems. J Cell Biochem 109:292-301. doi: 10.1002/jcb.22411
196. Roessler R, Smallwood S, Veenvliet J et al (2014) Detailed analysis of the genetic and epigenetic signature of iPS cell-derived mesodiencephalic dopaminergic neurons. Stem Cell Rep 2(4):520-533. doi: 10.1016/j.stemcr.2014.03.001
197. Bar-Nur O, Russ HA, Efrat S, Benvenisty N (2011) Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell 9:17-23. doi: 10.1016/j.stem.2011.06.007
198. Kim K, Doi A, Wen B et al (2010) Epigenetic memory in induced pluripotent stem cells. Nature 467:285-290. doi: 10.1038/nature09342
199. Momčilović O, Liu Q, Swistowski A et al (2013) Genome wide profiling of dopaminergic neurons derived from human embryonic and induced pluripotent Stem cells. Stem Cells Dev. doi: 10.1089/scd.2013.0412
200. Cooper O, Parmar M, Isacson O (2012) Chapter 13, characterization and criteria of embryonic stem and induced pluripotent stem cells for a dopamine replacement therapy. In: Stephen BD, Anders B (eds) Progress in brain research. Elsevier, London, pp 265-276
201. Grealish S, Jönsson ME, Li M et al (2010) The A9 dopamine neuron component in grafts of ventral mesencephalon is an important determinant for recovery of motor function in a rat model of Parkinson's disease. Brain 133:482-495. doi: 10.1093/brain/awp328
202. Thompson L, Barraud P, Andersson E et al (2005) Identification of dopaminergic neurons of nigral and ventral tegmental area subtypes in grafts of fetal ventral mesencephalon based on cell morphology, protein expression, and efferent projections. J Neurosci 25:6467-6477. doi: 10.1523/JNEUROSCI.1676-05.2005
203. Allodi I, Hedlund E (2014) Directed midbrain and spinal cord neurogenesis from pluripotent stem cells to model development and disease in a dish. Front Neurosci 8:109. doi: 10.3389/fnins.2014.00109
204. Roeper J (2013) Dissecting the diversity of midbrain dopamine neurons. Trends Neurosci 36:336-342. doi: 10.1016/j.tins.2013.03.003
205. Liss B, Roeper J (2008) Individual dopamine midbrain neurons: functional diversity and flexibility in health and disease. Brain Res Rev 58:314-321. doi: 10.1016/j.brainresrev.2007.10.004
206. Kirkeby A, Grealish S, Wolf DA et al (2012) Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep 1:703-714. doi: 10.1016/j.celrep.2012.04.009
207. Sánchez-Danés A, Consiglio A, Richaud Y et al (2012) Efficient generation of A9 midbrain dopaminergic neurons by lentiviral delivery of LMX1A in human embryonic stem cells and induced pluripotent stem cells. Hum Gene Ther 23:56-69. doi: 10.1089/hum.2011.054
208. Tian L-P, Zhang S, Zhang Y-J et al (2012) Lmx1b can promote the differentiation of embryonic stem cells to dopaminergic neurons associated with Parkinson's disease. Biotechnol Lett 34:1167-1174. doi: 10.1007/s10529-012-0888-5
209. Roy NS, Cleren C, Singh SK et al (2006) Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med 12:1259-1268. doi: 10.1038/nm1495
210. Narytnyk A, Verdon B, Loughney A et al (2014) Differentiation of human epidermal neural crest stem cells (hEPI-NCSC) into virtually homogenous populations of dopaminergic neurons. Stem Cell Rev. doi: 10.1007/s12015-013-9493-9
211. Mendez I, Sanchez-Pernaute R, Cooper O et al (2005) Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson's disease. Brain 128:1498-1510. doi: 10.1093/brain/awh510
212. Fu Y, Yuan Y, Halliday G et al (2012) A cytoarchitectonic and chemoarchitectonic analysis of the dopamine cell groups in the substantia nigra, ventral tegmental area, and retrorubral field in the mouse. Brain Struct Funct 217:591-612. doi: 10.1007/s00429-011-0349-2
213. Reyes S, Fu Y, Double K et al (2012) GIRK2 expression in dopamine neurons of the substantia nigra and ventral tegmental area. J Comp Neurol 520:2591-2607. doi: 10.1002/cne.23051
214. Greene JG, Dingledine R, Greenamyre JT (2005) Gene expression profiling of rat midbrain dopamine neurons: implications for selective vulnerability in Parkinsonism. Neurobiol Dis 18:19-31. doi: 10.1016/j.nbd.2004.10.003
215. Grimm J, Mueller A, Hefti F, Rosenthal A (2004) Molecular basis for catecholaminergic neuron diversity. PNAS 101:13891-13896. doi: 10.1073/pnas.0405340101
216. D'Amato RJ, Lipman ZP, Snyder SH (1986) Selectivity of the parkinsonian neurotoxin MPTP: toxic metabolite MPP+ binds to neuromelanin. Science 231:987-989
217. D'Amato RJ, Alexander GM, Schwartzman RJ et al (1987) Evidence for neuromelanin involvement in MPTP-induced neurotoxicity. Nature 327:324-326. doi: 10.1038/327324a0
218. Fishell G, Heintz N (2013) The neuron identity problem: form meets function. Neuron 80:602-612. doi: 10.1016/j.neuron.2013.10.035
219. Stamatakis AM, Jennings JH, Ung RL et al (2013) A unique population of ventral tegmental area neurons inhibits the lateral habenula to promote reward. Neuron 80:1039-1053. doi: 10.1016/j.neuron.2013.08.023
220. Lammel S, Hetzel A, Häckel O et al (2008) Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57:760-773. doi: 10.1016/j.neuron.2008