The Notch target genes Hey1 and Hey2 are required for embryonic vascular development.

By A. Fischer, N. Schumacher, M. Maier, M. Sendtner, M. Gessler. Genes & Development, 2004

694 citations recorded by the source corpus.

The Delta-Notch signaling pathway plays a central role in the development of most vertebrate organs. The Hey family of bHLH transcription factors are direct targets of Notch signaling. Loss of Hey2 in the mouse leads to cardiac defects with high postnatal lethality. We have now generated a mouse Hey1 knockout that has no apparent phenotypic defect. The combined loss of Hey1 and Hey2, however, results in embryonic death after embryonic day 9.5 (E9.5) with a global lack of vascular remodeling and massive hemorrhage. Initial vasculogenesis appears unaffected, but all subsequently developing major vessels in the embryo and yolk sac are either small or absent. Furthermore, the placental labyrinth completely lacks embryonic blood vessels. Similar vascular defects are observed in Jagged1 and Notch1 knockout mice. In the latter we found Hey1 and Hey2 expression in yolk sacs to be strongly reduced. Remaining large arteries in both Notch1 and Hey1/Hey2 knockout mice fail to express the arterial endothelial markers CD44, neuropilin1, and ephrin-B2. This indicates that Hey1/Hey2 are essential transducers of Notch signals in cardiovascular development that may mediate arterial cell fate decision.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d4d88cb566d20d499cd2bbf2e5e9dc8c870d4d04

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In Molecular Biology

1. Stefanie Dimmeler
2. A. Zeiher
3. D. Stainier
4. R. Mostoslavsky
5. M. Potente
6. E. Dejana
7. F. Alt
8. Leigh Coultas

Citations in the corpus

• Adam10 is essential for early embryonic cardiovascular development (2010, background): “nocopied theNotch1 andNotch targets knockouts (Krebs et al., 2000; Fischer et al., 2004; Timmerman et al., 2004; Limbourg et al., 2005; Grego-Bessa et al., 2007), but also showed downregulated expression of Notch target gene Snail and Bmp2 in the cardiac tissues.”
• Dosage-sensitive requirement for mouse Dll4 in artery development. (2004, background): “…gave no obvious phenotype alone, although Notch1/Notch4 double mutant embryos did show severe vascular remodeling defects (Krebs et al. 2000), which were also observed, to a lesser degree, in Hey1/Hey2 double mutants, the putative downstream targets of Notch signaling (Fischer et al. 2004).”
• Endothelial cells and VEGF in vascular development (2005, background): “Double mutation of Hes1 and Hey1, mammalian orthologues of gridlock, also produces loss of arterial markers and vascular shunt”
• RBP-Jκ/SHARP Recruits CtIP/CtBP Corepressors To Silence Notch Target Genes (2005, background): “Similar defects are observed in Jagged1 and Notch1 knockout mice (7).”
• SIRT1 controls endothelial angiogenic functions during vascular growth. (2007, background): “…which is the human homolog of the zebrafish gene gridlock, is an important regulator of endothelial gene expression and differentiation (Chi et al. 2003), and mice homozygous for a combined loss of Hey1 and Hey2 are embryonically lethal due to defects in vascular development (Fischer et al. 2004).”
• The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. (2009, background): “, 2004), Notch effector Rbpj and Mib, and Hey1/Hey2 double mutants (Fischer et al., 2004; Kokubo et al., 2004; Koo et al., 2005; Krebs et al., 2004).”
• Molecular control of endothelial cell behaviour during blood vessel morphogenesis (2011, background): “For example, Notch-mediated expression of the hairy- and enhancer of split-related with YRPW motif (HEY) basic helix–loop–helix transcription factor genes, HEY1 and HEY2 , promotes arterial differentiatio”
• Notch signaling in the mammalian central nervous system: insights from mouse mutants (2005, background): “Herp1 −/− Herp2 −/− double mutants have recently been described, and although the analysis focused on vascular defects, the authors noted that the neural tube was substantially thinner in mutant”