title: Foxa1 and foxa2 are required for the maintenance of dopaminergic properties in ventral midbrain neurons at late embryonic stages.
abstract: The maintained expression of transcription factors throughout the development of mesodiencephalic dopaminergic (mDA) neurons suggests multiple roles at various stages in development. Two members of the forkhead/winged helix transcription factor family, Foxa1 and Foxa2, have been recently shown to have an important influence in the early development of mDA neurons. Here we present data demonstrating that these genes are also involved in the later maintenance of the mDA system. We conditionally removed both genes in postmitotic mDA neurons using the dopamine transporter-cre mouse. Deletion of both Foxa1 and Foxa2 resulted in a significant reduction in the number of tyrosine hydroxylase (TH)-positive mDA neurons. The decrease was predominantly observed in the substantia nigra region of the mDA system, which led to a loss of TH+ fibers innervating the striatum. Further analysis demonstrated that the reduction in the number of TH+ cells in the mutant mice was not due to apoptosis or cell-fate change. Using reporter mouse lines, we found that the mDA neurons were still present in the ventral midbrain, but that they had lost much of their dopaminergic phenotype. The majority of these neurons remained in the ventral mesencephalon until at least 18 months of age. Chromatin immunoprecipitation suggested that the loss of the mDA phenotype is due to a reduction in the binding of the nuclear orphan receptor, Nurr-1 to the promoter region of TH. These results extend previous findings and demonstrate a later role for Foxa genes in regulating the maintenance of dopaminergic phenotype in mDA neurons.
authors: Developmental Neurobiology, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom.
authors: Simon R W
authors: SR
authors: Stott
authors: Emmanouil
authors: E
authors: Metzakopian
authors: Wei
authors: W
authors: Lin
authors: Klaus H
authors: KH
authors: Kaestner
authors: Rene
authors: R
authors: Hen
authors: Siew-Lan
authors: SL
authors: Ang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D048429:Cell Size; D047369:Chromatin Immunoprecipitation; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D059290:Dopaminergic Neurons / Q000502:physiology*; D004622:Embryo, Mammalian; D005684:Gait / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000172:deficiency / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000172:deficiency / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008164:Luminescent Proteins / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology* / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009412:Nerve Fibers / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D022661:RNA, Untranslated; C054562:yellow fluorescent protein, Bacteria; D051542:Hepatocyte Nuclear Factor 3-beta; D014446:Tyrosine 3-Monooxygenase
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