The Role of Otx Genes in Progenitor Domains of Ventral Midbrain

  • Antonio SimeoneEmail author
  • Eduardo Puelles
  • Dario Acampora
  • Daniela Omodei
  • Pietro Mancuso
  • Luca Giovanni Di Giovannantonio
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 651)


The mesencephalic dopaminergic (mesDA) neurons play a relevant role in the control of movement, behaviour and cognition. Indeed loss and/or abnormal development of mesDA neurons is responsible for Parkinson’s disease as well as for addictive and psychiatric disorders. A wealth of information has been provided on gene functions involved in the molecular mechanism controlling identity, fate and survival of mesDA neurons. Collectively, these studies are contributing to a growing knowledge of the genetic networks required for proper mesDA development, thus disclosing new perspectives for therapeutic approaches of mesDA disorders. Here we will focus on the control exerted by Otx genes in early decisions regulating the differentiation of progenitors located in the ventral midbrain. In this context, the regulatory network involving Otx functional interactions with signalling molecules and transcription factors required to promote or prevent the development of mesDA neurons will be analyzed in detail.


Ventral Midbrain Conditional Mutant Progenitor Domain Molecular Code Ventral Neural Tube 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dahlstrom A, Fuxe K. Localization of monoamines in the lower brain stem. Experientia 1964; 20:398–399.CrossRefPubMedGoogle Scholar
  2. 2.
    Hökfelt T, Matensson A, Björklund S et al. Distributional maps of tyrosine hydroxylase-immunoreactive neurons in the rat brain. In: Björklund A, Hökfelt T, eds. Handbook of Chemical Neuroanatomy: Classical Transmitters in the CNS. Amsterdam: Elsevier, 1984; 2:227–379.Google Scholar
  3. 3.
    Björklund A, Lindvall O. Dopamine-contianing systems in the CNS. In: Biörklund A, Hökfelt eds. Handbook of Chemical Neuroanatomy: Classical Transmitters in the CNS. Amsterdam: Elsevier, 1984; 2:55–121.Google Scholar
  4. 4.
    Jellinger KA. The pathology of parkinson’s disease. Adv Neurol 2001; 86:55–72.PubMedGoogle Scholar
  5. 5.
    Egan MF, Weinberger DR. Neurobiology of schizophrenia. Curr Opin Neurobiol 1997; 7:701–707.CrossRefPubMedGoogle Scholar
  6. 6.
    Klockgether T. Parkinson’s disease: clinical aspects. Cell Tissue Res 2004; 318:115–120.CrossRefPubMedGoogle Scholar
  7. 7.
    von Bohlen und Halbach O, Schober A, Krieglstein K. Genes, proteins and neurotoxins involved in Parkinson’s disease. Prog Neurobiol 2004; 73:151–177.CrossRefGoogle Scholar
  8. 8.
    Kelley AE, Berridge KC. The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci 2002; 22:3306–3311.PubMedGoogle Scholar
  9. 9.
    Isacson O. On neuronal health. Trends Neurosci 1993; 16:306–308.CrossRefPubMedGoogle Scholar
  10. 10.
    Rubenstein JL, Shimamura K, Martinez S et al. Regionalization of the prosencephalic neural plate. Annu Rev Neurosci 1998; 21:445–477.CrossRefPubMedGoogle Scholar
  11. 11.
    Lumsden A, Krumlauf R. Patterning the vertebrate neuraxis. Science 1996; 274:1109–1115.CrossRefPubMedGoogle Scholar
  12. 12.
    Wurst W, Bally-Cuif L. Neural plate patterning: upstream and downstream of the isthmic organizer. Nat Rev Neurosci 2001; 2:99–108.CrossRefPubMedGoogle Scholar
  13. 13.
    Jessell TM. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat Rev Genet 2000; 1:20–29.CrossRefPubMedGoogle Scholar
  14. 14.
    Edlund T, Jessell TM. Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system. Cell 1999; 96:211–224.CrossRefPubMedGoogle Scholar
  15. 15.
    Briscoe J, Ericson J. Specification of neuronal fates in the ventral neural tube. Curr Opin Neurobiol 2001; 11:43–49.CrossRefPubMedGoogle Scholar
  16. 16.
    Ye W, Shimamura K, Rubenstein JL et al. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 1998; 93:755–766.CrossRefPubMedGoogle Scholar
  17. 17.
    Simeone A. Positioning the isthmic organizer where Otx2 and Gbx2 meet. Trends Genet 2000; 16:237–240.CrossRefPubMedGoogle Scholar
  18. 18.
    Prakash N, Wurst W. Development of dopaminergic neurons in the mammalian brain. Cell Mol Life Sci 2006; 63:187–206.CrossRefPubMedGoogle Scholar
  19. 19.
    Simeone A. Genetic control of dopaminergic neuron differentiation. Trends Neurosci 2005; 28:62–65; discussion 65–66.CrossRefPubMedGoogle Scholar
  20. 20.
    Smidt MP, Asbreuk CH, Cox JJ et al. A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat Neurosci 2000; 3:337–341.CrossRefPubMedGoogle Scholar
  21. 21.
    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; 95:4013–4018.CrossRefPubMedGoogle Scholar
  22. 22.
    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; 19:167–170.CrossRefPubMedGoogle Scholar
  23. 23.
    Smidt MP, van Schaick HS, Lanctot C et al. A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc Natl Acad Sci USA 1997; 94:13305–13310.CrossRefPubMedGoogle Scholar
  24. 24.
    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; 131:1145–1155.CrossRefPubMedGoogle Scholar
  25. 25.
    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; 130:2535–2542.CrossRefPubMedGoogle Scholar
  26. 26.
    Nunes I, Tovmasian LT, Silva RM et al. Pitx3 is required for development of substantia nigra dopaminergic neurons. Proc Natl Acad Sci USA 2003; 100:4245–4250.CrossRefPubMedGoogle Scholar
  27. 27.
    Simon HH, Saueressig H, Wurst W et al. Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J Neurosci 2001; 21:3126–3234.PubMedGoogle Scholar
  28. 28.
    Simeone A, Acampora D, Gulisano M et al. Nested expression domains of four homeobox genes in developing rostral brain. Nature 1992; 358:687–690.CrossRefPubMedGoogle Scholar
  29. 29.
    Simeone A, Acampora D, Mallamaci A et al. A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo. EMBO J 1993; 12:2735–2747.PubMedGoogle Scholar
  30. 30.
    Acampora D, Mazan S, Lallemand Y et al. Forebrain and midbrain regions are deleted in Otx2−/−mutants due to a defective anterior neuroectoderm specification during gastrulation. Development 1995; 121:3279–3290.PubMedGoogle Scholar
  31. 31.
    Acampora D, Mazan S, Avantaggiato V et al. Epilepsy and brain abnormalities in mice lacking the Otx1 gene. Nat Genet 1996; 14:218–222.CrossRefPubMedGoogle Scholar
  32. 32.
    Acampora D, Avantaggiato V, Tuorto F et al. Genetic control of brain morphogenesis through Otx gene dosage requirement. Development 1997; 124:3639–3650.PubMedGoogle Scholar
  33. 33.
    Martinez-Barbera JP, Signore M, Boyl PP et al. Regionalisation of anterior neuroectoderm and its competence in responding to forebrain and midbrain inducing activities depend on mutual antagonism between OTX2 and GBX2. Development 2001; 128:4789–4800.PubMedGoogle Scholar
  34. 34.
    Puelles E, Acampora D, Lacroix E et al. Otx dose-dependent integrated control of antero-posterior and dorso-ventral patterning of midbrain. Nat Neurosci 2003; 6:453–460.PubMedGoogle Scholar
  35. 35.
    Puelles E, Annino A, Tuorto F et al. Otx2 regulates the extent, identity and fate of neuronal progenitor domains in the ventral midbrain. Development 2004; 131:2037–2048.CrossRefPubMedGoogle Scholar
  36. 36.
    Prakash N, Brodski C, Naserke T et al. A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo. Development 2006; 133:89–98.CrossRefPubMedGoogle Scholar
  37. 37.
    Borgkvist A, Puelles E, Carta M et al. Altered dopaminergic innervation and amphetamine response in adult Otx2 conditional mutant mice. Mol Cell Neurosci 2006; 31:293–302.CrossRefPubMedGoogle Scholar
  38. 38.
    Puelles E, Acampora D, Gogoi R et al. Otx2 controls identity and fate of glutamatergic progenitors of the thalamus by repressing GABAergic differentiation. J Neurosci 2006; 26: 5955–5964.CrossRefPubMedGoogle Scholar
  39. 39.
    Acampora D, Simeone A. the TINS Lecture. Understanding the roles of Otx1 and Otx2 in the control of brain morphogenesis. Trends Neurosci 1999; 22:116–122.CrossRefPubMedGoogle Scholar
  40. 40.
    Simeone A, Puelles E, Acampora D. The Otx family. Curr Opin Genet Dev 2002; 12:409–415.CrossRefPubMedGoogle Scholar
  41. 41.
    Lawrence PA, Struhl G. Morphogens, Compartments and Pattern: Lessons from Drosophila? Cell 1996; 85:951–961.CrossRefPubMedGoogle Scholar
  42. 42.
    Martinez S, Wassef M, Alvarado-Mallart RM. Induction of a mesencephalic phenotype in the 2 day-old chick prosencephalon is preceded by the early expression of the homeobox gene en. Neuron 1991; 6:971–981.CrossRefPubMedGoogle Scholar
  43. 43.
    Crossley PH, Martinez S, Martin GR. Midbrain development induced by FGF8 in the chick embryo. Nature 1996; 380:66–68.CrossRefPubMedGoogle Scholar
  44. 44.
    Shimamura K, Rubenstein JL. Inductive interactions direct early regionalization of the mouse forebrain. Development 1997; 124:2709–2718.PubMedGoogle Scholar
  45. 45.
    Joyner AL, Liu A, Millet S. Otx2, Gbx2 and Fgf8 interact to position and maintain a mid-hindbrain organizer. Curr Opin Cell Biol 2000; 12:736–741.CrossRefPubMedGoogle Scholar
  46. 46.
    Rhinn M, Brand M. The midbrain-hindbrain boundary organizer. Curr Opin Neurobiol 2001; 11:34–42.CrossRefPubMedGoogle Scholar
  47. 47.
    Ye W, Bouchard M, Stone D et al. Distinct regulators control the expression of the mid-hindbrain organizer signal FGF8. Nature Neurosc 2001; 4:1175–1181.CrossRefGoogle Scholar
  48. 48.
    Suda Y, Matsuo I, Aizawa S. Cooperation between Otx1 and Otx2 genes in developmental patterning of rostral brain. Mech Dev 1997; 69:125–141.CrossRefPubMedGoogle Scholar
  49. 49.
    Acampora D, Avantaggiato V, Tuorto F et al. Visceral endodern-restricted translation of Otx1 mediates recovering of Otx2 requirements for specification of anterior neural plate and proper gastrulation. Development 1998; 125:5091–5104.PubMedGoogle Scholar
  50. 50.
    Broccoli V, Boncinelli E, Wurst W. The caudal limit of Otx2 expression positions the isthmic organizer. Nature 1999; 401:164–168.CrossRefPubMedGoogle Scholar
  51. 51.
    Wassarmann KM, Lewandoski M, Campbell K et al. Specification of the anterior hindbrain and establishment of a normal mid/hindbrain organizer dependent on Gbx2 gene function. Development 1997; 124:2923–2934.Google Scholar
  52. 52.
    Millet S, Campbell K, Epstein DJ et al. A role for Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Nature 1999; 401:161–164.CrossRefPubMedGoogle Scholar
  53. 53.
    Li YH, Joyner AL. Otx2 and Gbx2 are required for refinement and not induction of mid-hindbrain gene expression. Development 2001; 128:4979–4991.PubMedGoogle Scholar
  54. 54.
    Pilo Boyl P, Signore M, Acampora D et al. Forebrain and midbrain development requires epiblast-restricted Otx2 translational control mediated by its 3′ UTR. Development 2001; 128:2989–3000.Google Scholar
  55. 55.
    Li JY, Lao Z, Joyner AL. Changing requirements for Gbx2 in development of the cerebellum and maintenance of the mid/hindbrain organizer. Neuron 2002; 36:31–43.CrossRefPubMedGoogle Scholar
  56. 56.
    Agarwala S, Sanders TA, Ragsdale CW. Sonic hedgehog control of size and shape in midbrain pattern formation. Science 2001; 291:2147–2150.CrossRefPubMedGoogle Scholar
  57. 57.
    Heimbucher T, Murko C, Bajoghli B et al. Gbx2 and Otx2 interact with the WD40 domain of Groucho/Tle corepressors. Mol Cell Biol 2007; 27:340–51.CrossRefPubMedGoogle Scholar
  58. 58.
    Eberhard D, Jimenez G, Heavey B et al. Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family. EMBO J 2000; 19:2292–2303.CrossRefPubMedGoogle Scholar
  59. 59.
    Fisher AL, Caudy M. Groucho proteins: transcriptional corepressors for specific subsets of DNA-binding transcription factors in vertebrates and invertebrates. Genes Dev 1998; 12:1931–1940.CrossRefPubMedGoogle Scholar
  60. 60.
    Fisher AL, Ohsako S, Caudy M. The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain. Mol Cell Biol 1996; 16:2670–2677.PubMedGoogle Scholar
  61. 61.
    Muhr J, Andersson E, Persson M et al. Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube. Cell 2001; 104:861–873.CrossRefPubMedGoogle Scholar
  62. 62.
    Zhu CC, Dyer MA, Uchikawa M et al. Six3-mediated auto repression and eye development requires its interaction with members of the Groucho-related family of corepressors. Development 2002; 129:2835–2849.PubMedGoogle Scholar
  63. 63.
    Wolpert L. Positional information and the spatial pattern of cellular differentiation. J Theor Biol 1969; 25:1–47.CrossRefPubMedGoogle Scholar
  64. 64.
    Briscoe J, Sussel L, Serup P et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature 1999; 398:622–627.CrossRefPubMedGoogle Scholar
  65. 65.
    Pattyn A, Vallstedt A, Dias JM et al. Coordinated temporal and spatial control of motor neuron and serotonergic neuron generation from a common pool of CNS progenitors. Genes Dev 2003; 17:729–737.CrossRefPubMedGoogle Scholar
  66. 66.
    Brodski C, Weisenhorn DM, Signore M et al. Location and size of dopaminergic and serotonergic cell populations are controlled by the position of the midbrain-hindbrain organizer. J Neurosci 2003; 23:4199–4207.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Antonio Simeone
    • 1
    • 2
    Email author
  • Eduardo Puelles
    • 3
  • Dario Acampora
    • 1
    • 2
  • Daniela Omodei
    • 1
  • Pietro Mancuso
    • 1
  • Luca Giovanni Di Giovannantonio
    • 1
  1. 1.CEINGE Biotecnologie Avanzate and SEMM European School of Molecular MedicineNaplesItaly
  2. 2.Institute of Genetics and BiophysicsNaplesItaly
  3. 3.Instituto de Neurociencias de AlicanteCSIC and Universidad Miguel HernàndezSant Joan d’AlacantSpain

Personalised recommendations