Partial rescue of defects in Cited2-deficient embryos by HIF-1α heterozygosity

Bing Xu, Yongqiu Doughman, Mona Turakhia, Weihong Jiang, Chad E. Landsettle, Faton H. Agani, Gregg L. Semenza, Michiko Watanabe, Yu Chung Yang

Research output: Contribution to journalArticlepeer-review

Abstract

Hypoxia inducible factor-1 (HIF-1) initiates key cellular and tissue responses to physiological and pathological hypoxia. Evidence from in vitro and structural analyses supports a critical role for Cited2 in down-regulating HIF-1-mediated transcription by competing for binding with oxygen-sensitive HIF-1α to transcriptional co-activators CBP/p300. We previously detected elevated expression of HIF-1 target genes in Cited2-/- embryonic hearts, indicating that Cited2 inhibits HIF-1 transactivation in vivo. In this study, we show for the first time that highly hypoxic cardiac regions in mouse embryos corresponded to the sites of defects in Cited2-/- embryos and that defects of the outflow tract, interventricular septum, cardiac vasculature, and hyposplenia were largely rescued by HIF-1α haploinsufficiency. The hypoxia of the outflow tract and interventricular septum peaked at E13.5 and dissipated by E15.5 in wild-type hearts, but persisted in E15.5 Cited2-/- hearts. The persistent hypoxia and abnormal vasculature in the myocardium of interventricular septum in E15.5 Cited2-/- hearts were rescued with decreased HIF-1α gene dosage. Accordingly, mRNA levels of HIF-1-responsive genes were reduced in Cited2-/- embryonic hearts by HIF-1α heterozygosity. These findings suggest that a precise level of HIF-1 transcriptional activity critical for normal development is triggered by differential hypoxia and regulated through feedback inhibition by Cited2.

Original languageEnglish (US)
Pages (from-to)130-140
Number of pages11
JournalDevelopmental biology
Volume301
Issue number1
DOIs
StatePublished - Jan 1 2007

Keywords

  • Cited2
  • Heart development
  • Hypoxia
  • Vascular endothelial growth factor-A

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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