Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner.
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.
Ferri
Anna L M
AL
Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Lin
Wei
W
Mavromatakis
Yannis E
YE
Wang
Julie C
JC
Sasaki
Hiroshi
H
Whitsett
Jeffrey A
JA
Ang
Siew-Lan
SL
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D018628:Gene Dosage / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics; D008297:Male; D008636:Mesencephalon / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011247:Pregnancy; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D004298:Dopamine; D051541:Hepatocyte Nuclear Factor 3-alpha; D051542:Hepatocyte Nuclear Factor 3-beta; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; C102938:Neurog2 protein, mouse