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.

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

“…Altogether, these data demonstrate that our mouse model specifically addresses the role of FOXA1/2 in mDA neurons. Previous studies have demonstrated roles for FOXA1/2 in initiating and maintaining the molecular identity of mDA neurons during development at the transcriptional level (15)(16)(17)(18)(19). We therefore determined whether FOXA1/2 are still required to maintain the expression of transcripts that are pivotal for mDA neuron function, such as mRNA of Th, Ddc, Slc18a2, Slc6a3, and Drd2 genes, by real-time quantitative PCR (rt-qPCR).…”

“…We have also found that FOXA1/2 play a crucial role in the generation of mDA neurons during early and late development, regulating both their specification and differentiation in a dose-dependent manner (15). FOXA1/2 operate in successive feedforward loops with different cofactors to regulate the expression of distinct target genes in neuronal progenitors and immature neurons (16)(17)(18)(19). There is accumulating evidence that transcription factors regulating the specification and differentiation of mDA neurons retain expression in the adult brain (20).…”

Genome-wide characterization of Foxa2 targets reveals upregulation of floor plate genes and repression of ventrolateral genes in midbrain dopaminergic progenitors

“…Foxa2 and Shh signaling have similar roles in ventral midbrain patterning (Blaess et al, 2006;Lin et al, 2009); however, we recently found that Foxa2 also attenuates Shh signaling by repressing the expression of its intracellular transducers Gli1, Gli2 and Gli3 (Mavromatakis et al, 2011). We therefore examined whether targets of Gli1 that were previously identified by ChIP-chip in neural progenitors (Vokes et al, 2007) are also bound by Foxa2.…”

“…In addition, Foxa2 also bound sites in Gli2 and Gli3 (Mavromatakis et al, 2011) that are not known to be bound by Gli1 (Fig. 3), suggesting the possibility that Foxa2 directly regulates all three Gli genes.…”

“…Ten million NestinLmx1a-transfected ES cells were used to prepare chromatin and a Foxa2-specific antibody was used for ChIP (Mavromatakis et al, 2011). Following sequencing, peak calling was performed using MACS with a threshold of FDR<5%, resulting in a dataset of 9160 high confidence peaks.…”