| Popis: |
The establishment of a functional circulatory system is required for post-implantation development during murine embryogenesis. Previous studies in loss of function mouse models have shown that FOXO1, a Forkhead family transcription factor, is required for yolk sac vascular remodeling and survival beyond embryonic day (E) 11. Here, we demonstrate that loss ofFoxO1in E8.25 endothelial cells results in increasedSprouty2andSprouty4transcripts, reduced expression of arterial genes, and decreasedFlk1/Vegfr2mRNA levels without affecting overall endothelial cell identity, survival, or proliferation. Using aDll4-BAC-nlacZreporter line, we found that one of the earliest expressed arterial genes,Delta like 4(Dll4), is significantly reduced in the yolk sac ofFoxO1mutants without being substantially affected in the embryo proper. We show that in the yolk sac, FOXO1 not only binds directly to a subset of previously identifiedSprouty2gene regulatory elements (GREs), as well as newly identified, evolutionarily conservedSprouty4GREs, but can also repress their expression. Additionally, over expression ofSprouty4in transient transgenic embryos largely recapitulates reduced expression of arterial genes seen in endothelialFoxO1mutant mouse embryos. Together, these data reveal a novel role for FOXO1 as a key early transcriptional repressor controlling both pre-flow arterial specification and subsequent vessel remodeling within the murine yolk sac. |
