title: Foxa1 and Foxa2 positively and negatively regulate Shh signalling to specify ventral midbrain progenitor identity.
abstract: Foxa2, a member of the Foxa family of forkhead/winged helix family of transcription factors, has previously been shown to be an upstream positive regulator of Shh expression in many different tissues. Recent studies also strongly suggest that Foxa2 specify cell fate by inhibiting the expression of cell fate determinants such as Helt1 and Nkx2.2. In this paper, phenotypic analyses of Wnt1cre; Foxa2flox/flox embryos in the midbrain have demonstrated a novel role for Foxa2 and its related family member, Foxa1, to attenuate Shh signalling by inhibiting the expression of its intracellular transducer, Gli2, at the transcriptional level. Chromatin immunoprecipitation experiments indicate that Foxa2 binds to genomic regions of Gli2 and likely regulates its expression in a direct manner. Our studies, involving loss and gain of function studies in mice, also provided further insights into the gene regulatory interactions among Foxa1, Foxa2 and Shh in ventral midbrain progenitors that contribute to midbrain patterning. Altogether, these data indicate that Foxa1 and Foxa2 contribute to the specification of ventral midbrain progenitor identity by regulating Shh signalling in a positive and negative manner.
authors.affiliation: Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Yannis E
authors.initials: YE
authors.lastname: Mavromatakis
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Metzakopian
authors.forename: Anna L M
authors.initials: AL
authors.lastname: Ferri
authors.forename: Carol H
authors.initials: CH
authors.lastname: Yan
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sasaki
authors.forename: Jeff
authors.initials: J
authors.lastname: Whisett
authors.forename: Siew-Lan
authors.initials: SL
authors.lastname: Ang
mesh_terms: D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D016678:Genome / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D000072079:Patched Receptors; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D029961:Zebrafish Proteins; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051541:Hepatocyte Nuclear Factor 3-alpha; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; C000715627:Nkx2-2 protein, mouse; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; C000715630:nkx2.2b protein, zebrafish; D051542:Hepatocyte Nuclear Factor 3-beta