Establishing a functional circulatory system is required for post-implantation development during murine embryogenesis. Previous studies in loss-of-function mouse models showed that FOXO1, a Forkhead family transcription factor, is required for yolk sac (YS) vascular remodeling and survival beyond embryonic day (E) 11. Here, we demonstrate that at E8.25, loss of FoxO1 in Tie2-cre expressing cells resulted in increased Sprouty2 and Sprouty4, reduced arterial genes, and reduced Flk1/Vegfr2 transcripts without affecting overall endothelial cell identity, survival, or proliferation. Using a Dll4-BAC-nlacZ reporter line, we found that one of the earliest expressed arterial genes, Delta like 4, is significantly reduced in FoxO1 mutant YS without being substantially affected in the embryo proper. We show that FOXO1 binds directly to previously identified Sprouty2 gene regulatory elements (GREs) and newly identified, evolutionarily conserved Sprouty4 GREs to repress their expression. Furthermore, overexpression of Sprouty4 in transient transgenic embryos largely recapitulates reduced arterial genes seen in conditional FoxO1 mutants. Together, these data reveal a novel role for FOXO1 as a key transcriptional repressor regulating both pre-flow arterial specification and subsequent vessel remodeling within the murine YS.
FOXO1 represses Sprouty2 and Sprouty4 expression to promote arterial specification and vascular remodeling in the mouse yolk sac
Authors who contributed equally to the work
- Award Group:
- Funder(s): National Institutes of Health
- Award Id(s): R01 HD099026
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Nanbing Li-Villarreal, Rebecca Lee Yean Wong, Monica D. Garcia, Ryan S. Udan, Ross A. Poché, Tara L. Rasmussen, Alexander M. Rhyner, Joshua D. Wythe, Mary E. Dickinson; FOXO1 represses Sprouty2 and Sprouty4 expression to promote arterial specification and vascular remodeling in the mouse yolk sac. Development 2022; dev.200131. doi: https://doi.org/10.1242/dev.200131
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