Foxa1 and Foxa2 Transcription Factors Regulate Differentiation of Midbrain Dopaminergic Neurons

  • Siew-Lan AngEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 651)


Midbrain dopaminergic neurons (mDA), comprising the substantia nigra pars compacta (A8), the ventral tegmental area (A9) and the retrorubal field (A10) subgroups, are generated from floor plate progenitors, rostral to the isthmic boundary. Floor plate progenitors are specified to become mDA progenitors between embryonic days 8.0 and 10.5. Subsequently these progenitors undergo neuronal differentiation in two phases, termed early and late differentiation to generate immature and mature neurons respectively. Genes that regulate specification, early and late phases of differentiation of mDA cells have recently been identified. Among them, the forkhead winged helix transcription factors Foxal and Foxa2 (Foxa1/2), have been shown to have essential and dose dependent roles at multiple phases of development. In this chapter, I will summarize recent studies demonstrating a role for Foxa1/2 in regulating the neuronal specification and differentiation of mDA progenitors and conclude with projections on future directions of this area of research.


Mature Neuron Mutant Embryo Immature Neuron Definitive Endoderm Midbrain Dopaminergic Neuron 
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.
    Weigel D, Jurgens G, Kuttner F et al. The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the drosophila embryo. Cell 1989; 57:645–58.CrossRefPubMedGoogle Scholar
  2. 2.
    Kaestner KH, Knochel W, Martinez DE. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev 2000; 14:142–6.PubMedGoogle Scholar
  3. 3.
    Pohl BS, Knochel W. Of Fox and Frogs: Fox (fork head/winged helix) transcription factors in xenopus development. Gene 2005; 344:21–32.CrossRefPubMedGoogle Scholar
  4. 4.
    Friedman JR, Kaestner KH. The Foxa family of transcription factors in development and metabolism. Cell Mol Life Sci 2006; 63:2317–28.CrossRefPubMedGoogle Scholar
  5. 5.
    Panowski SH, Wolff S, Aguilaniu H et al. PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature 2007; 447:550–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Cao C, Liu Y, Lehmann M. Fork head controls the timing and tissue selectivity of steroid-induced developmental cell death. J Cell Biol 2007; 176:843–52.CrossRefPubMedGoogle Scholar
  7. 7.
    Ferri AL, Lin W, Mavromatakis YE et al. Foxal and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development 2007; 134:2761–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Jacob J, Ferri AL, Milton C et al. Transcriptional repression coordinates the temporal switch from motor to serotonergic neurogenesis. Nat Neurosci 2007.Google Scholar
  9. 9.
    Ang SL, Wierda A, Wong D et al. The formation and maintenance of the definitive endoderm lineage in the mouse: Involvement of HNF3/forkhead proteins. Development 1993; 119:1301–15.PubMedGoogle Scholar
  10. 10.
    Monaghan AP, Kaestner KH, Grau E et al. Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm. Development 1993; 119:567–78.PubMedGoogle Scholar
  11. 11.
    Sasaki H, Hogan BL. HNF-3 beta as a regulator of floor plate development. Cell 1994; 76:103–15.CrossRefPubMedGoogle Scholar
  12. 12.
    Thuret S, Bhatt L, O’Leary DD et al. Identification and developmental analysis of genes expressed by dopaminergic neurons of the substantia nigra pars compacta. Mol Cell Neurosci 2004; 25:394–405.CrossRefPubMedGoogle Scholar
  13. 13.
    Wijchers PJ, Hoekman MF, Burbach JP et al. Identification of forkhead transcription factors in cortical and dopaminergic areas of the adult murine brain. Brain Res 2006; 1068:23–33.CrossRefPubMedGoogle Scholar
  14. 14.
    Sasaki H, Hui C, Nakafuku M et al. A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development 1997; 124:1313–22.PubMedGoogle Scholar
  15. 15.
    Epstein DJ, McMahon AP, Joyner AL. Regionalization of Sonic hedgehog transcription along the anteroposterior axis of the mouse central nervous system is regulated by Hnf3-dependent and-independent mechanisms. Development 1999; 126:281–92.PubMedGoogle Scholar
  16. 16.
    Weinstein DC, Ruiz i Altaba A, Chen WS et al. The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo. Cell 1994; 78:575–88.CrossRefPubMedGoogle Scholar
  17. 17.
    Norton WH, Mangoli M, Lele Z et al. Monorail/Foxa2 regulates floorplate differentiation and specification of oligodendrocytes, serotonergic raphe neurones and cranial motoneurones. Development 2005; 132:645–58.CrossRefPubMedGoogle Scholar
  18. 18.
    Clevidence DE, Zhou H, Lau LF et al. The-4 kilobase promoter region of the winged helix transcription factor HNF-3alpha gene elicits transgene expression in mouse embryonic hepatic and intestinal diverticula. Int J Dev Biol 1998; 42:741–6.PubMedGoogle Scholar
  19. 19.
    Sinner D, Rankin S, Lee M et al. Sox17 and beta-catenin cooperate to regulate the transcription of endodermal genes. Development 2004: 131:3069–80.CrossRefPubMedGoogle Scholar
  20. 20.
    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; 80:95–101.CrossRefPubMedGoogle Scholar
  21. 21.
    Ye W, Shimamura K, Rubenstein JL et al. FGF and Shh signals control dopaminergic and scrotonergic cell fate in the anterior neural plate. Cell 1998; 93:755–66.CrossRefPubMedGoogle Scholar
  22. 22.
    Ono Y et al. Differences in neurogenic potential in floor plate cells along an anteroposterior location: midbrain dopaminergic neurons originate from mesencephalic floor plate cells. Development 2007; 134:3213–25.CrossRefPubMedGoogle Scholar
  23. 23.
    Andersson E, Jensen JB, Parmar M et al. Development of the mesencephalic dopaminergic neuron system is compromised in the absence of neurogenin 2. Development 2006; 133:507–16.CrossRefPubMedGoogle Scholar
  24. 24.
    Kele J, Simplicio N, Ferri AL et al. Neurogenin 2 is required for the development of ventral midbrain dopaminergic neurons. Development 2006; 133:495–505.CrossRefPubMedGoogle Scholar
  25. 25.
    Andersson E, Tryggvason U, Deng Q et al. Identification of intrinsic determinants of midbrain dopamine neurons. Cell 2006; 124:393–405.CrossRefPubMedGoogle Scholar
  26. 26.
    Vernay B, Koch M, Vaccarino F et al. Otx2 regulates subtype specification and neurogenesis in the midbrain. J Neurosci 2005; 25:4856–67.CrossRefPubMedGoogle Scholar
  27. 27.
    Ang SL, Rossant J. HNF-3 beta is essential for node and notochord formation in mouse development. Cell 1994; 78:561–74.CrossRefPubMedGoogle Scholar
  28. 28.
    Kaestner KH, Katz J, Liu Y et al. Inactivation of the winged helix transcription factor HNF3alpha affects glucose homeostasis and islet glucagon gene expression in vivo. Genes Dev 1999; 13:495–504.CrossRefPubMedGoogle Scholar
  29. 29.
    Hirabayashi Y, Itoh Y, Tabata H et al. The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development 2004; 131:2791–801.CrossRefPubMedGoogle Scholar
  30. 30.
    Lee JE, Wu SF, Goering LM et al. Canonical Wnt signaling through Lef1 is required for hypothalamic neurogenesis. Development 2006; 133:4451–61.CrossRefPubMedGoogle Scholar
  31. 31.
    Garcia-Campmany L, Marti E. The TGFbeta intracellular effector Smad3 regulates neuronal differentiation and cell fate specification in the developing spinal cord. Development 2007; 134:65–75.CrossRefPubMedGoogle Scholar
  32. 32.
    Wallen A, Perlmann T. Transcriptional control of dopamine neuron development. Ann NY Acad Sci 2003; 991:48–60.PubMedCrossRefGoogle Scholar
  33. 33.
    Alberi L, Sgado P, Simon HH. Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons. Development 2004; 131:3229–36.CrossRefPubMedGoogle Scholar
  34. 34.
    Wan H, Dingle S, Xu Y et al. Compensatory roles of Foxa1 and Foxa2 during lung morphogenesis. J Biol Chem 2005; 280:13809–16.CrossRefPubMedGoogle Scholar
  35. 35.
    Lee CS, Friedman JR, Fulmer JT et al. The initiation of liver development is dependent on Foxa transcription factors. Nature 2005; 435:944–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Besnard V, Wert SE, Hull WM et al. Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues. Gene Expr Patterns 2004; 5:193–208.CrossRefPubMedGoogle Scholar
  37. 37.
    Wolfrum C, Stoffel M. Coactivation of Foxa2 through Pgc-1beta promotes liver fatty acid oxidation and triglyceride/VLDL secretion. Cell Metab 2006; 3:99–110.CrossRefPubMedGoogle Scholar
  38. 38.
    Cirillo LA et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol Cell 2002; 9:279–89.CrossRefPubMedGoogle Scholar
  39. 39.
    Shimizu S, Kondo M, Miyamoto Y et al. Foxa (HNF3) up-regulates vitronectin expression during retinoic acid-induced differentiation in mouse neuroblastoma Neuro2a cells. Cell Struct Funct 2002; 27:181–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Foucher I, Montesinos ML, Volovitch M et al. Joint regulation of the MAP1B promoter by HNF3beta/Foxa2 and Engrailed is the result of a highly conserved mechanism for direct interaction of homeoproteins and Fox transcription factors. Development 2003; 130:1867–76.CrossRefPubMedGoogle Scholar
  41. 41.
    Shim EY, Woodcock C, Zaret KS. Nucleosome positioning by the winged helix transcription factor HNF3. Genes Dev 1998; 12:5–10.CrossRefPubMedGoogle Scholar
  42. 42.
    Updike DL, Mango SE. Temporal regulation of foregut development by HTZ-1/H2A.Z and PHA-4/FoxA. PLoS Genet 2006; 2:e161.CrossRefPubMedGoogle Scholar
  43. 43.
    Gaudet J, Mango SE. Regulation of organogenesis by the Caenorhabditis elegans Foxa protein PHA-4. Science 2002; 295:821–5.CrossRefPubMedGoogle Scholar
  44. 44.
    Ang SL. Transcriptional control of midbrain dopaminergic neuron development. Development 2006; 133:3499–506.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.NIMRLondon

Personalised recommendations