Disease relevance of Hey1

• 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 [1].
• Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition [2].
• Furthermore, expression of Notch1 and its effector Hey-1 gene in human prostate adenocarcinomas were found significantly down-regulated compared to normal control tissues [3].

Psychiatry related information on Hey1

• Moreover, young adults of Hesr1 knockout mice showed a decrease in spontaneous locomotor activity and a reduction in exploratory behavior or behavioral responses to novelty in the open-field, and elevated plus-maze tests [4].

High impact information on Hey1

• This indicates that Hey1/Hey2 are essential transducers of Notch signals in cardiovascular development that may mediate arterial cell fate decision [1].
• In the latter we found Hey1 and Hey2 expression in yolk sacs to be strongly reduced [1].
• In the Hesr1-misexpressing heart, the boundaries of the AV canal are poorly defined, and the expression levels of specific markers of the AV myocardium, Bmp2 and Tbx2, are either very weak or undetectable [5].
• Mammalian Fbw7 thus appears to play an indispensable role in negative regulation of the Notch4-Hey1 pathway and is required for vascular development [6].
• Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity [7].

Biological context of Hey1

• Hey genes (Hey1, Hey2 and HeyL) encode a new group of basic helix-loop-helix transcription factors that are related to the hairy/Enhancer of split genes [8].
• In the present study, we cloned and characterized the promoter region of the human and mouse Hey1 gene [8].
• Identification of BOIP, a novel cDNA highly expressed during spermatogenesis that encodes a protein interacting with the orange domain of the hairy-related transcription factor HRT1/Hey1 in Xenopus and mouse [9].

Anatomical context of Hey1

• Here we report that combined inactivation of Hey1 and HeyL, two primary target genes of Notch, causes severe heart malformations, including membranous ventricular septal defects and dysplastic atrioventricular and pulmonary valves [2].
• We showed that bone morphogenic protein 2 stimulated expression of Hey1, a direct Notch target gene, in mouse MC3T3 and C2C12 cells, in human mesenchymal cells, and in mouse calvaria [7].
• Small interfering RNA-mediated inhibition of Hey1 induction led to an increase in osteoblast matrix mineralization, suggesting that Hey1 is a negative regulator of osteoblast maturation [7].
• HRT1 and HRT2 transcripts were also detected in precursors of the pharyngeal arches and subsequently in the pharyngeal clefts [10].
• Recent evidence demonstrates that hesr1 and hesr2 function redundantly in epithelial-to-mesenchymal transformation during atrioventricular valve formation and maintenance of trabecular cells in the heart ventricles, and in arterial-venous differentiation of blood vessels [11].

Associations of Hey1 with chemical compounds

• To investigate functions of the HESR1 gene in the dopaminergic nervous system in vivo, we analyzed the expressions of dopamine-related genes in the postnatal day 0 whole brains of Hesr1 knockout mice by real-time RT-PCR analysis [4].
• HRT-1 and LRT-1 mice also differed significantly in chronic tolerance development to four doses of ethanol [12].

Regulatory relationships of Hey1

• In vitro studies have revealed that the Notch signaling pathway directly regulates transcription of hairy and enhancer of split-related (hesr) genes, encoding basic helix-loop-helix transcription factors [13].

Other interactions of Hey1

• However, mutational analysis of individual hesr genes has so far failed to elucidate their role in all Notch-mediated cardiovascular signaling events [14].
• This negative regulation is apparently achieved via interaction with Runx2: Hey1 completely abrogated Runx2 transcriptional activity [7].
• Microarray and subsequent expression analyses in mice identified two transcription factors, Hey1 and Tcf7, with in vitro and in vivo expression characteristics very similar to Cbfa1 [15].

Analytical, diagnostic and therapeutic context of Hey1

• Misexpression of Hesr1 and Hesr2 by electroporation in mouse brain at embryonic day 13.5 transiently maintains neural precursor cells and thereby increases late-born neurons, which are located in the superficial layers [16].
• In situ hybridization analysis indicated that all hesr genes are expressed in the developing retina, but only hesr2 expression is associated spatially with gliogenesis [17].
• To assess the functional role of hesr genes in cardiovascular development, we generated mice with a targeted disruption of the hesr2 gene and used echocardiography to analyze heart function of the mutant mice [13].

References