Foxa1 and Foxa2 positively and negatively regulate Shh signalling to specify ventral midbrain progenitor identity

Yannis E. Mavromatakis, Wei Lin, Emmanouil Metzakopian, Anna L M Ferri, Carol H. Yan, Hiroshi Sasaki, Jeff Whisett, Siew Lan Ang

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)90-103
Number of pages14
JournalMechanisms of Development
Volume128
Issue number1-2
DOIs
Publication statusPublished - Jan 2011

Keywords

  • Cell fate specification
  • Dorsal-ventral patterning
  • Forkhead genes
  • Gli
  • Midbrain
  • Nkx2.2

ASJC Scopus subject areas

  • Developmental Biology
  • Embryology

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    Mavromatakis, Y. E., Lin, W., Metzakopian, E., Ferri, A. L. M., Yan, C. H., Sasaki, H., Whisett, J., & Ang, S. L. (2011). Foxa1 and Foxa2 positively and negatively regulate Shh signalling to specify ventral midbrain progenitor identity. Mechanisms of Development, 128(1-2), 90-103. https://doi.org/10.1016/j.mod.2010.11.002