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First published online 27 June 2007
doi: 10.1242/dev.000141

Development 134, 2761-2769 (2007)
Published by The Company of Biologists 2007
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Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner

Anna L. M. Ferri1,*, Wei Lin1,*, Yannis E. Mavromatakis1, Julie C. Wang1, Hiroshi Sasaki2, Jeffrey A. Whitsett3 and Siew-Lan Ang1,{dagger}

1 Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
2 Laboratory for Embryonic Induction, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
3 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.

{dagger} Author for correspondence (e-mail: sang{at}nimr.mrc.ac.uk)

Accepted 24 May 2007

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.

Key words: Forkhead genes, Cell fate specification, Differentiation, Dopaminergic, Midbrain, Gene dosage




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[Abstract] [Full Text] [PDF]


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