FOXO1 represses sprouty 2 and sprouty 4 expression to promote arterial specification and vascular remodeling in the mouse yolk sac

Development. 2022 Apr 1;149(7):dev200131. doi: 10.1242/dev.200131. Epub 2022 Apr 1.


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 sprouty 2 (Spry2) and Spry4 expression, reduced arterial gene expression and reduced Kdr (also known as Vegfr2 and Flk1) 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 Spry2 gene regulatory elements (GREs) and newly identified, evolutionarily conserved Spry4 GREs to repress their expression. Furthermore, overexpression of Spry4 in transient transgenic embryos largely recapitulates the reduced expression of 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.

Keywords: Arterial specification; Dll4; Foxo1; Sprouty.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arteries
  • Embryo, Mammalian / metabolism
  • Endothelial Cells / metabolism
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Vascular Remodeling* / genetics
  • Yolk Sac* / metabolism


  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Nerve Tissue Proteins