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Midbrain dopaminergic neurons: control of their cell fate by the engrailed transcription factors

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Abstract

As for any other cell population, the development, cell fate, and properties of mesencephalic dopaminergic (mesDA) neurons are ultimately controlled at the transcriptional level. The genes for two transcription factors Engrailed-1 (En1) and Engrailed-2 (En2) play an essential role in the development and maintenance of these cells. They belong to a family of genes that have been investigated in Drosophila for more than half a century. The products of these genes are all characterized by homeotic tissue transformation and a highly conserved protein sequence, the homeobox. En1 and En2 act upon at least two steps of the differentiation of mesDA neurons. They take part in the regionalization event, which gives rise to the neuroepithelium that provides the precursor cells in the ventral midbrain with the fibroblast growth factor 8 signal necessary for their induction. Additionally, these genes are required in postmitotic mesDA neurons in which they are expressed from embryonic day 12 continuously into adulthood. In mutant mice homozygous null for En1 and En2, the neurons are generated in the ventral midbrain, become postmitotic, and begin to express their neurotransmitter phenotype. However, thereafter, they rapidly die by apoptosis. Cell mixing experiments in vitro and in vivo have demonstrated that the engrailed requirement for the survival of mesDA neurons is cell-autonomous. The inactivation of engrailed by RNA interference induces apoptosis in less than 24 h. These data suggest that the engrailed genes control an essential mechanism for the survival of mesDA neurons.

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References

  • Ades SE, Sauer RT (1994) Differential DNA-binding specificity of the engrailed homeodomain: the role of residue 50. Biochemistry 33:9187–9194

    CAS  PubMed  Google Scholar 

  • Alberi L, Sgado P, Simon HH (2004) Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons. Development 131:3229–3236

    Google Scholar 

  • Altman J, Bayer SA (1981) Development of the brain stem in the rat. V. Thymidine—radiographic study of the time of origin of neurons in the midbrain tegmentum. J Comp Neurol 198:677–716

    CAS  PubMed  Google Scholar 

  • Barak O, Lazzaro MA, Lane WS, Speicher DW, Picketts DJ, Shiekhattar R (2003) Isolation of human NURF: a regulator of engrailed gene expression. EMBO J 22:6089–6100

    Article  CAS  PubMed  Google Scholar 

  • Bourbon HM, Martin-Blanco E, Rosen D, Kornberg TB (1995) Phosphorylation of the Drosophila engrailed protein at a site outside its homeodomain enhances DNA binding. J Biol Chem 270:11130–11139

    Article  CAS  PubMed  Google Scholar 

  • Brasted A (1941) An analysis of the expression of the mutant “engrailed” in Drosophila melanogaster. Genetics 26:347–373

    Google Scholar 

  • Burrill JD, Moran L, Goulding MD, Saueressig H (1997) PAX2 is expressed in multiple spinal cord interneurons, including a population of EN1+ interneurons that require PAX6 for their development. Development 124:4493–4503

    CAS  PubMed  Google Scholar 

  • Castillo SO, Baffi JD, Palkovits M, Goldstein DS, Kopin IJ, Witta J, Magnuson MA, Nikodem VM (1998) Dopamine biosynthesis is selectively abolished in substantia nigra/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene. Mol Cell Neurosci 11:36–46

    Article  CAS  PubMed  Google Scholar 

  • Condron BG, Patel NH, Zinn K (1994) Engrailed controls glial/neuronal cell fate decisions at the midline of the central nervous system. Neuron 13:541–554

    Article  CAS  PubMed  Google Scholar 

  • Cosgaya JM, Aranda A, Cruces J, Martin-Blanco E (1998) Neuronal differentiation of PC12 cells induced by engrailed homeodomain is DNA-binding specific and independent of MAP kinases. J Cell Sci 111:2377–2384

    CAS  PubMed  Google Scholar 

  • Davidson D, Graham E, Sime C, Hill R (1988) A gene with sequence similarity to Drosophila engrailed is expressed during the development of the neural tube and vertebrae in the mouse. Development 104:305–316

    CAS  PubMed  Google Scholar 

  • Davis CA, Noble-Topham SE, Rossant J, Joyner AL (1988) Expression of the homeo box-containing gene En-2 delineates a specific region of the developing mouse brain. Genes Dev 2:361–371

    CAS  PubMed  Google Scholar 

  • Davis CA, Holmyard DP, Millen KJ, Joyner AL (1991) Examining pattern formation in mouse, chicken and frog embryos with an En-specific antiserum. Development 111:287–298

    CAS  PubMed  Google Scholar 

  • Desplan C, Theis J, O’Farrell PH (1985) The Drosophila developmental gene, engrailed, encodes a sequence-specific DNA binding activity. Nature 318:630–635

    CAS  PubMed  Google Scholar 

  • Desplan C, Theis J, O’Farrell PH (1988) The sequence specificity of homeodomain-DNA interaction. Cell 54:1081–1090

    Article  CAS  PubMed  Google Scholar 

  • Dijk MA van, Murre C (1994) Extradenticle raises the DNA binding specificity of homeotic selector gene products. Cell 78:617–624

    Article  PubMed  Google Scholar 

  • Di Porzio U, Zuddas A, Cosenza-Murphy DB, Barker JL (1990) Early appearance of tyrosine hydroxylase immunoreactive cells in the mesencephalon of mouse embryos. Int J Dev Neurosci 8:523–532

    Article  PubMed  Google Scholar 

  • Dolecki GJ, Humphreys T (1988) An engrailed class homeo box gene in sea urchins. Gene 64:21–31

    Article  CAS  PubMed  Google Scholar 

  • Duman-Scheel M, Patel NH (1999) Analysis of molecular marker expression reveals neuronal homology in distantly related arthropods. Development 126:2327–2334

    CAS  PubMed  Google Scholar 

  • Eker R (1929) The recessive mutant engrailed in Drosophila melanogaster. Hereditas 12:217–222

    Google Scholar 

  • Ekker M, Wegner J, Akimenko MA, Westerfield M (1992) Coordinate embryonic expression of three zebrafish engrailed genes. Development 116:1001–1010

    CAS  PubMed  Google Scholar 

  • Fjose A, McGinnis WJ, Gehring WJ (1985) Isolation of a homeo box-containing gene from the engrailed region of Drosophila and the spatial distribution of its transcripts. Nature 313:284–289

    CAS  PubMed  Google Scholar 

  • Force A, Lynch M, Pickett FB, Amores A, Yan YL, Postlethwait J (1999) Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151:1531–1545

    CAS  PubMed  Google Scholar 

  • Foster GA, Schultzberg M, Kokfelt T, Goldstein M, Hemmings HC Jr, Ouimet CC, Walaas SI, Greengard P (1988) Ontogeny of the dopamine and cyclic adenosine-3′:5′-monophosphate-regulated phosphoprotein (DARPP-32) in the pre- and postnatal mouse central nervous system. Int J Dev Neurosci 6:367–386

    Article  CAS  PubMed  Google Scholar 

  • Friedman GC, O’Leary DD (1996) Eph receptor tyrosine kinases and their ligands in neural development. Curr Opin Neurobiol 6:127–133

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Bellido A, Santamaria P (1972) Developmental analysis of the wing disc in the mutant engrailed of Drosophila melanogaster. Genetics 72:87–104

    CAS  PubMed  Google Scholar 

  • Gay NJ, Poole S, Kornberg T (1988a) Association of the Drosophila melanogaster engrailed protein with specific soluble nuclear protein complexes. EMBO J 7:4291–4297

    CAS  PubMed  Google Scholar 

  • Gay NJ, Poole SJ, Kornberg TB (1988b) The Drosophila engrailed protein is phosphorylated by a serine-specific protein kinase. Nucleic Acids Res 16:6637–6647

    CAS  PubMed  Google Scholar 

  • Gemel J, Jacobsen C, MacArthur CA (1999) Fibroblast growth factor-8 expression is regulated by intronic engrailed and Pbx1-binding sites. J Biol Chem 274:6020–6026

    Article  CAS  PubMed  Google Scholar 

  • Han K, Levine MS, Manley JL (1989) Synergistic activation and repression of transcription by Drosophila homeobox proteins. Cell 56:573–583

    CAS  PubMed  Google Scholar 

  • Hanks M, Wurst W, Anson-Cartwright L, Auerbach AB, Joyner AL (1995) Rescue of the En-1 mutant phenotype by replacement of En-1 with En-2. Science 269:679–682

    CAS  PubMed  Google Scholar 

  • Hanks MC, Loomis CA, Harris E, Tong CX, Anson-Cartwright L, Auerbach A, Joyner A (1998) Drosophila engrailed can substitute for mouse Engrailed1 function in mid-hindbrain, but not limb development. Development 125:4521–4530

    CAS  PubMed  Google Scholar 

  • Harzsch S, Miller J, Benton J, Dawirs RR, Beltz B (1998) Neurogenesis in the thoracic neuromeres of two crustaceans with different types of metamorphic development. J Exp Biol 201:2465–2479

    PubMed  Google Scholar 

  • Hidalgo A (1998) Growth and patterning from the engrailed interface. Int J Dev Biol 42:317–324

    CAS  PubMed  Google Scholar 

  • Holland LZ, Kene M, Williams NA, Holland ND (1997) Sequence and embryonic expression of the amphioxus engrailed gene (AmphiEn): the metameric pattern of transcription resembles that of its segment-polarity homolog in Drosophila. Development 124:1723–1732

    CAS  PubMed  Google Scholar 

  • Hortsch M, Bieber AJ, Patel NH, Goodman CS (1990) Differential splicing generates a nervous system-specific form of Drosophila neuroglian. Neuron 4:697–709

    CAS  PubMed  Google Scholar 

  • Itasaki N, Nakamura H (1996) A role for gradient en expression in positional specification on the optic tectum. Neuron 16:55–62

    Article  CAS  PubMed  Google Scholar 

  • Joliot A, Trembleau A, Raposo G, Calvet S, Volovitch M, Prochiantz A (1997) Association of engrailed homeoproteins with vesicles presenting caveolae-like properties. Development 124:1865–1875

    CAS  PubMed  Google Scholar 

  • Joliot A, Maizel A, Rosenberg D, Trembleau A, Dupas S, Volovitch M, Prochiantz A (1998) Identification of a signal sequence necessary for the unconventional secretion of engrailed homeoprotein. Curr Biol 8:856–863

    Article  CAS  PubMed  Google Scholar 

  • Joyner AL, Martin GR (1987) En-1 and En-2, two mouse genes with sequence homology to the Drosophila engrailed gene: expression during embryogenesis. Genes Dev 1:29–38

    CAS  PubMed  Google Scholar 

  • Joyner AL, Kornberg T, Coleman KG, Cox DR, Martin GR (1985) Expression during embryogenesis of a mouse gene with sequence homology to the Drosophila engrailed gene. Cell 43:29–37

    Article  CAS  PubMed  Google Scholar 

  • Joyner AL, Skarnes WC, Rossant J (1989) Production of a mutation in mouse En-2 gene by homologous recombination in embryonic stem cells. Nature 338:153–156

    Article  CAS  PubMed  Google Scholar 

  • Joyner AL, Liu A, Millet S (2000) Otx2, Gbx2 and Fgf8 interact to position and maintain a mid-hindbrain organizer. Curr Opin Cell Biol 12:736–741

    Article  CAS  PubMed  Google Scholar 

  • Kamb A, Weir M, Rudy B, Varmus H, Kenyon C (1989) Identification of genes from pattern formation, tyrosine kinase, and potassium channel families by DNA amplification. Proc Natl Acad Sci USA 86:4372–4376

    CAS  PubMed  Google Scholar 

  • Kissinger CR, Liu BS, Martin-Blanco E, Kornberg TB, Pabo CO (1990) Crystal structure of an engrailed homeodomain—DNA complex at 2.8 Å resolution: a framework for understanding homeodomain—DNA interactions. Cell 63:579–590

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi M, Fujioka M, Tolkunova EN, Deka D, Abu-Shaar M, Mann RS, Jaynes JB (2003) Engrailed cooperates with extradenticle and homothorax to repress target genes in Drosophila. Development 130:741–751

    Article  CAS  PubMed  Google Scholar 

  • Kohl A, Giese KP, Mohajeri MH, Montag D, Moos M, Schachner M (1992) Analysis of promoter activity and 5′ genomic structure of the neural cell adhesion molecule L1. J Neurosci Res 32:167–177

    CAS  PubMed  Google Scholar 

  • Kornberg T (1981) Engrailed: a gene controlling compartment and segment formation in Drosophila. Proc Natl Acad Sci USA 78:1095–1099

    CAS  PubMed  Google Scholar 

  • Koster JG, Eizema K, Peterson-Maduro LJ, Stegeman BI, Destree OH (1996) Analysis of Wnt/engrailed signaling in Xenopus embryos using biolistics. Dev Biol 173:348–352

    Article  CAS  PubMed  Google Scholar 

  • Kuner JM, Nakanishi M, Ali Z, Drees B, Gustavson E, Theis J, Kauvar L, Kornberg T, O’Farrell PH (1985) Molecular cloning of engrailed: a gene involved in the development of pattern in Drosophila melanogaster. Cell 42:309–316

    CAS  PubMed  Google Scholar 

  • Lee KJ, Jessell TM (1999) The specification of dorsal cell fates in the vertebrate central nervous system. Annu Rev Neurosci 22:261–294

    Article  CAS  PubMed  Google Scholar 

  • Liu A, Joyner AL (2001) EN and GBX2 play essential roles downstream of FGF8 in patterning the mouse mid/hindbrain region. Development 128:181–191

    CAS  PubMed  Google Scholar 

  • Logan C, Hanks MC, Noble-Topham S, Nallainathan D, Provart NJ, Joyner AL (1992) Cloning and sequence comparison of the mouse, human, and chicken engrailed genes reveal potential functional domains and regulatory regions. Dev Genet 13:345–358

    CAS  PubMed  Google Scholar 

  • Logan C, Wizenmann A, Drescher U, Monschau B, Bonhoeffer F, Lumsden A (1996) Rostral optic tectum acquires caudal characteristics following ectopic engrailed expression. Curr Biol 6:1006–1014

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Corrales NL, Sonstegard TS, Smith TP (1998) Comparative gene mapping: cytogenetic localization of PROC, EN1, ALPI, TNP1, and IL1B in cattle and sheep reveals a conserved rearrangement relative to the human genome. Cytogenet Cell Genet 83:35–38

    CAS  PubMed  Google Scholar 

  • Lowe CJ, Wray GA (1997) Radical alterations in the roles of homeobox genes during echinoderm evolution. Nature 389:718–721

    Article  CAS  PubMed  Google Scholar 

  • Lundell MJ, Chu-LaGraff Q, Doe CQ, Hirsh J (1996) The engrailed and huckebein genes are essential for development of serotonin neurons in the Drosophila CNS. Mol Cell Neurosci 7:46–61

    Article  CAS  PubMed  Google Scholar 

  • Maizel A, Bensaude O, Prochiantz A, Joliot A (1999) A short region of its homeodomain is necessary for engrailed nuclear export and secretion. Development 126:3183–3190

    CAS  PubMed  Google Scholar 

  • Maizel A, Tassetto M, Filhol O, Cochet C, Prochiantz A, Joliot A (2002) Engrailed homeoprotein secretion is a regulated process. Development 129:3545–3553

    CAS  PubMed  Google Scholar 

  • Manak JR, Scott MP (1994) A class act: conservation of homeodomain protein functions. Development Suppl:61–77

    Google Scholar 

  • Marie B, Bacon JP, Blagburn JM (2000) Double-stranded RNA interference shows that engrailed controls the synaptic specificity of identified sensory neurons. Curr Biol 10:289–292

    Article  CAS  PubMed  Google Scholar 

  • Matise MP, Joyner AL (1997) Expression patterns of developmental control genes in normal and engrailed-1 mutant mouse spinal cord reveal early diversity in developing interneurons. J Neurosci 17:7805–7816

    Google Scholar 

  • Millen KJ, Wurst W, Herrup K, Joyner AL (1994) Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse engrailed-2 mutants. Development 120:695–706

    CAS  PubMed  Google Scholar 

  • Ohkuma Y, Horikoshi M, Roeder RG, Desplan C (1990) Binding site-dependent direct activation and repression of in vitro transcription by Drosophila homeodomain proteins. Cell 61:475–484

    Article  CAS  PubMed  Google Scholar 

  • Patel NH, Martin-Blanco E, Coleman KG, Poole SJ, Ellis MC, Kornberg TB, Goodman CS (1989) Expression of engrailed proteins in arthropods, annelids, and chordates. Cell 58:955–968

    Article  CAS  PubMed  Google Scholar 

  • Peltenburg LT, Murre C (1997) Specific residues in the Pbx homeodomain differentially modulate the DNA-binding activity of Hox and engrailed proteins. Development 124:1089–1098

    CAS  PubMed  Google Scholar 

  • Puelles E, Acampora D, Lacroix E, Signore M, Annino A, Tuorto F, Filosa S, Corte G, Wurst W, Ang SL, Simeone A (2003) Otx dose-dependent integrated control of antero-posterior and dorso-ventral patterning of midbrain. Nat Neurosci 6:453–460

    CAS  PubMed  Google Scholar 

  • Puelles E, Annino A, Tuorto F, Usiello A, Acampora D, Czerny T, Brodski C, Ang SL, Wurst W, Simeone A (2004) Otx2 regulates the extent, identity and fate of neuronal progenitor domains in the ventral midbrain. Development 131:2037–2048

    Google Scholar 

  • Rhinn M, Brand M (2001) The midbrain–hindbrain boundary organizer. Curr Opin Neurobiol 11:34–42

    Article  CAS  PubMed  Google Scholar 

  • Ristoratore F, Carl M, Deschet K, Richard-Parpaillon L, Boujard D, Wittbrodt J, Chourrout D, Bourrat F, Joly JS (1999) The midbrain–hindbrain boundary genetic cascade is activated ectopically in the diencephalon in response to the widespread expression of one of its components, the medaka gene Ol-eng2. Development 126:3769–3779

    CAS  PubMed  Google Scholar 

  • Rubenstein JL, Martinez S, Shimamura K, Puelles L (1994) The embryonic vertebrate forebrain: the prosomeric model. Science 266:578–580

    CAS  PubMed  Google Scholar 

  • Saucedo-Cardenas O, Quintana-Hau JD, Le WD, Smidt MP, Cox JJ, De Mayo F, Burbach JP, Conneely OM (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

    Article  CAS  PubMed  Google Scholar 

  • Saueressig H, Burrill J, Goulding M (1999) Engrailed-1 and netrin-1 regulate axon pathfinding by association interneurons that project to motor neurons. Development 126:4201–4212

    CAS  PubMed  Google Scholar 

  • Scholtz G, Patel NH, Dohle W (1994) Serially homologous engrailed stripes are generated via different cell lineages in the germ band of amphipod crustaceans (Malacostraca, Peracarida). Int J Dev Biol 38:471–478

    CAS  PubMed  Google Scholar 

  • Sechrist J, Bronner-Fraser M (1991) Birth and differentiation of reticular neurons in the chick hindbrain: ontogeny of the first neuronal population. Neuron 7:947–963

    CAS  PubMed  Google Scholar 

  • Serrano N, Maschat F (1998) Molecular mechanism of polyhomeotic activation by engrailed. EMBO J 17:3704–3713

    Google Scholar 

  • Shamim H, Mahmood R, Logan C, Doherty P, Lumsden A, Mason I (1999) Sequential roles for Fgf4, En1 and Fgf8 in specification and regionalisation of the midbrain. Development 126:945–959

    CAS  PubMed  Google Scholar 

  • Shigetani Y, Funahashi JI, Nakamura H (1997) En-2 regulates the expression of the ligands for Eph type tyrosine kinases in chick embryonic tectum. Neurosci Res 27:211–217

    Article  CAS  PubMed  Google Scholar 

  • Siegler MV, Jia XX (1999) Engrailed negatively regulates the expression of cell adhesion molecules connectin and neuroglian in embryonic Drosophila nervous system. Neuron 22:265–276

    Article  CAS  PubMed  Google Scholar 

  • Siegler MV, Pankhaniya RR (1997) Engrailed protein is expressed in interneurons but not motor neurons of the dorsal unpaired median group in the adult grasshopper. J Comp Neurol 388:658–668

    Article  CAS  PubMed  Google Scholar 

  • Simon HH, Saueressig H, Wurst W, Goulding MD, O’Leary DD (2001) Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J Neurosci 21:3126–3134

    CAS  PubMed  Google Scholar 

  • Simon HH, Bhatt L, Gherbassi D, Sgado P, Alberi L (2003) Midbrain dopaminergic neurons: determination of their developmental fate by transcription factors. Ann N Y Acad Sci 991:36–47

    CAS  PubMed  Google Scholar 

  • Smith ST, Jaynes JB (1996) A conserved region of engrailed, shared among all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, mediates active transcriptional repression in vivo. Development 122:3141–3150

    CAS  PubMed  Google Scholar 

  • Smits SM, Ponnio T, Conneely OM, Burbach JP, Smidt MP (2003) Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons. Eur J Neurosci 18:1731–1738

    Article  PubMed  Google Scholar 

  • Tokunaga C (1961) The differentiation of a secondary sex comb under the influence of the gene engrailed in Drosophila melanogaster. Genetics 46:157–176

    CAS  PubMed  Google Scholar 

  • Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP, Perlmann T (2003) Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423:555–560

    Article  CAS  PubMed  Google Scholar 

  • Wanninger A, Haszprunar G (2001) The expression of an engrailed protein during embryonic shell formation of the tusk-shell, Antalis entalis (Mollusca, Scaphopoda). Evol Dev 3:312–321

    Article  CAS  PubMed  Google Scholar 

  • Webster PJ, Mansour TE (1992) Conserved classes of homeodomains in Schistosoma mansoni, an early bilateral metazoan. Mech Dev 38:25–32

    Article  CAS  PubMed  Google Scholar 

  • Wedeen CJ, Weisblat DA (1991) Segmental expression of an engrailed-class gene during early development and neurogenesis in an annelid. Development 113:805–814

    CAS  PubMed  Google Scholar 

  • Wedeen CJ, Price DJ, Weisblat DA (1991) Cloning and sequencing of a leech homolog to the Drosophila engrailed gene. FEBS Lett 279:300–302

    Article  CAS  PubMed  Google Scholar 

  • Wray CG, Jacobs DK, Kostriken R, Vogler AP, Baker R, DeSalle R (1995) Homologues of the engrailed gene from five molluscan classes. FEBS Lett 365:71–74

    Article  CAS  PubMed  Google Scholar 

  • Wurst W, Bally-Cuif L (2001) Neural plate patterning: upstream and downstream of the isthmic organizer. Nat Rev Neurosci 2:99–108

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Ye W, Shimamura K, Rubenstein JL, Hynes MA, Rosenthal A (1998) FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93:755–766

    Article  CAS  PubMed  Google Scholar 

  • Yue Y, Widmer DA, Halladay AK, Cerretti DP, Wagner GC, Dreyer JL, Zhou R (1999) Specification of distinct dopaminergic neural pathways: roles of the eph family receptor EphB1 and ligand ephrin-B2. J Neurosci 19:2090–2101

    CAS  PubMed  Google Scholar 

  • Zec N, Rowitch DH, Bitgood MJ, Kinney HC (1997) Expression of the homeobox-containing genes EN1 and EN2 in human fetal midgestational medulla and cerebellum. J Neuropathol Exp Neurol 56:236–242

    CAS  PubMed  Google Scholar 

  • Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250

    Article  CAS  PubMed  Google Scholar 

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  1. Horst H. Simon, Sandrine Thuret & Lavinia Alberi

    Present address: Laboratory of Genetics, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA

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  1. Department of Neuroanatomy, Interdisciplinary Center of Neuroscience, University of Heidelberg, Im Neuenheimer Feld 307, 69120, Heidelberg, Germany

    Horst H. Simon, Sandrine Thuret & Lavinia Alberi

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Correspondence to Horst H. Simon.

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Our work was supported by a Biofuture grant from the Federal Ministry for Education and Research (H.S., L.A.) and a fellowship from the Boehringer Ingelheim foundation (S.T.)

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Simon, H.H., Thuret, S. & Alberi, L. Midbrain dopaminergic neurons: control of their cell fate by the engrailed transcription factors. Cell Tissue Res 318, 53–61 (2004). https://doi.org/10.1007/s00441-004-0973-8

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