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Dev Biol 2014 Mar 01;3871:28-36. doi: 10.1016/j.ydbio.2014.01.003.
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A potential molecular pathogenesis of cardiac/laterality defects in Oculo-Facio-Cardio-Dental syndrome.

Tanaka K , Kato A , Angelocci C , Watanabe M , Kato Y .

Pitx2 is the last effector of the left-right (LR) cascade known to date and plays a crucial role in the patterning of LR asymmetry. In Xenopus embryos, the expression of Pitx2 gene in the left lateral plate mesoderm (LPM) is directly regulated by Xnr1 signaling, which is mediated by Smads and FoxH1. Previous studies suggest that the suppression of Pitx2 gene in the left LPM is a potential cause of cardiac/laterality defects in Oculo-Facio-Cardio-Dental (OFCD) syndrome, which is known to be caused by mutations in BCL6 co-repressor (BCOR) gene. Recently, our work has revealed that the BCL6/BCOR complex blocks Notch-dependent transcriptional activity to protect the expression of Pitx2 in the left LPM from the inhibitory activity of Notch signaling. These studies indicated that uncontrolled Notch activity in the left LPM caused by dysfunction of BCOR may result in cardiac/laterality defects of OFCD syndrome. However, this Notch-dependent inhibitory mechanism of Pitx2 gene transcription still remains unknown. Here we report that transcriptional repressor ESR1, which acts downstream of Notch signaling, inhibits the expression of Pitx2 gene by binding to a left side-specific enhancer (ASE) region in Pitx2 gene and recruiting histone deacetylase 1 (HDAC1) to this region. Once HDAC1 is tethered, histone acetyltransferase p300 is no longer recruited to the Xnr1-dependent transcriptional complex on the ASE region, leading to the suppression of Pitx2 gene in the left LPM. The study presented here uncovers the regulatory mechanism of Pitx2 gene transcription which may contribute to an understanding of pathogenesis of OFCD syndrome.

PubMed ID: 24440151
PMC ID: PMC3951022
Article link: Dev Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: arsl ep300 esr1 foxh1.2 hdac1 mst1 myc nodal1 notch1 pitx2 smad2 smad4
GO keywords: heart development [+]

Disease Ontology terms: microphthalmia
Phenotypes: Xla Wt + esr1-GR + DEX (Fig. 2 B C) [+]

Article Images: [+] show captions
References [+] :
Aalfs, Cataracts, radiculomegaly, septal heart defects and hearing loss in two unrelated adult females with normal intelligence and similar facial appearance: confirmation of a syndrome? 1996, Pubmed