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

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