Hairy/enhancer of split-related proteins, such as HEY1, are basic helix-loop-helix (bHLH) transcription factors implicated in cell fate decision and boundary formation. HEY genes are direct transcriptional targets of the Notch (see 600275) signaling pathways in Drosophila and vertebrates.

By searching EST databases with TLE (see 600189)-like bHLH sequences, Kokubo et al. (1999) identified mouse, human, and Drosophila homologs of a novel gene family, which the authors termed hairy/enhancer of split-related (HESR). Independently, Leimeister et al. (1999) identified the same gene family, which they termed HEY because the deduced proteins have a substitution of tyrosine (Y) for the first tryptophan (W) in the conserved C-terminal tetrapeptide of bHLH hairy and enhancer of split proteins, the Drosophila groucho-binding WRPW motif. In addition, the proteins substitute glycine for proline at the sixth position of the basic region of their DNA-binding bHLH domains. The murine and human HEY1 proteins have 299 and 304 amino acids, respectively, and are identical in the 55-amino acid bHLH domain and in the last 13 amino acids of the C terminus, and 98% identical in the 44-amino acid 'orange' domain. Using in situ hybridization, Kokubo et al. (1999) and Leimeister et al. (1999) determined that mouse Hey1 is expressed at embryonic day 8 in the presomitic mesoderm and is widely expressed in tissues throughout gestation.

By differential display of genes upregulated during mouse kidney development, Steidl et al. (2000) cloned Hey1. Northern blot analysis detected a 2.2-kb transcript differentially expressed in all mouse tissues examined and in day-12.5 mouse embryos.

Kokubo et al. (1999) showed that mice lacking the Notch ligand delta-1 (Dll1; see 602768) did not express Hesr1 in the presomitic and somitic mesoderm.

Steidl et al. (2000) determined that the mouse Hey1 gene contains 5 exons and spans 3.5 kb. The human HEY1 gene has a similar structure.

By FISH and radiation hybrid analysis, Steidl et al. (2000) mapped the HEY1 gene to chromosome 8q21. They mapped the mouse Hey1 gene close to the centromere of chromosome 3.

Fischer et al. (2004) found that Hey1 knockout in mice resulted in no apparent phenotypic defect. However, the combined loss of Hey1 and Hey2 (604674) resulted in embryonic death with a global lack of vascular remodeling and massive hemorrhage. Initial vasculogenesis appeared to be unaffected, but all subsequently developing major vessels in the embryo and yolk sac were either small or absent. Furthermore, the placental labyrinth completely lacked embryonic blood vessels. Similar vascular defects had been observed in Jagged1 (601920) and Notch1 knockout mice. Hey1 and Hey2 expression was strongly reduced in the yolk sacs of Notch1 knockout mice. The remaining large arteries in both Notch1 and Hey1/Hey2 knockout mice failed to express several arterial endothelial markers, suggesting that Hey1 and Hey2 are transducers of Notch signals in cardiovascular development.