Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner

Anna L M Ferri, Wei Lin, Yannis E. Mavromatakis, Julie C. Wang, Hiroshi Sasaki, Jeffrey A. Whitsett, Siew Lan Ang

Research output: Contribution to journalArticle

Abstract

The role of transcription factors in regulating the development of midbrain dopaminergic (mDA) neurons is intensively studied owing to the involvement of these neurons in diverse neurological disorders. Here we demonstrate novel roles for the forkhead/winged helix transcription factors Foxa1 and Foxa2 in the specification and differentiation of mDA neurons by analysing the phenotype of Foxa1 and Foxa2 single- and double-mutant mouse embryos. During specification, Foxa1 and Foxa2 regulate the extent of neurogenesis in mDA progenitors by positively regulating Ngn2 (Neurog2) expression. Subsequently, Foxa1 and Foxa2 regulate the expression of Nurr1 (Nr4a2) and engrailed 1 in immature neurons and the expression of aromatic L-amino acid decarboxylase and tyrosine hydroxylase in mature neurons during early and late differentiation of midbrain dopaminergic neurons. Interestingly, genetic evidence indicates that these functions require different gene dosages of Foxa1 and Foxa2. Altogether, our results demonstrate that Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner.

Original languageEnglish
Pages (from-to)2761-2769
Number of pages9
JournalDevelopment
Volume134
Issue number15
DOIs
Publication statusPublished - Aug 2007

Keywords

  • Cell fate specification
  • Differentiation
  • Dopaminergic
  • Forkhead genes
  • Gene dosage
  • Midbrain

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

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    Ferri, A. L. M., Lin, W., Mavromatakis, Y. E., Wang, J. C., Sasaki, H., Whitsett, J. A., & Ang, S. L. (2007). Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development, 134(15), 2761-2769. https://doi.org/10.1242/dev.000141