Disease relevance of Hey2

• 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].
• Mice lacking Hey2 develop cardiac hypertrophy, often associated with congenital heart defects, whereas combined Hey1/Hey2 deficiency leads to severe vascular defects and embryonic lethality around embryonic day E9 [2].
• Tetralogy of fallot and other congenital heart defects in Hey2 mutant mice [3].
• Mouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in Hey2 -/- mice [4].
• Isolated myocytes from transgenic mice demonstrate a similar resistance to phenylephrine-induced hypertrophy in vitro, providing further evidence that the protective effect of CHF1/Hey2 is mediated at the myocyte level [5].

High impact information on Hey2

• This indicates that Hey1/Hey2 are essential transducers of Notch signals in cardiovascular development that may mediate arterial cell fate decision [1].
• The Notch target genes Hey1 and Hey2 are required for embryonic vascular development [1].
• In the latter we found Hey1 and Hey2 expression in yolk sacs to be strongly reduced [1].
• Our results indicate that CHF1 plays an important role in regulation of ventricular septation in mammalian heart development and is important for normal myocardial contractility [6].
• Adenovirus-mediated expression of Hrt2 suppressed mRNA expression of ANF and other cardiac-specific genes in cultured cardiomyocytes [7].

Chemical compound and disease context of Hey2

• Induction of the hypertrophy marker genes ANF, BNP, and beta-MHC in the transgenic cells is concurrently suppressed in vivo and in vitro, demonstrating that the induction of hypertrophy-associated genes is repressed by CHF1/Hey2 [5].

Biological context of Hey2

• We have generated a knockout of the murine Hey2 (gridlock) gene to analyze the mammalian phenotype [4].
• Here, we use gene targeting to determine the developmental functions of mouse Hey2, a Hey family member that is expressed during the embryonic development of the heart, arteries, and other organs [3].
• The other members of the Hey gene family, Hey2 and HeyL, also possess RBP-Jkappa binding sites and they are similarly responsive to Notch signaling [8].
• 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].
• Transfection of CHF1/Hey2 into neonatal cardiomyocytes suppresses activation of an ANF reporter plasmid by the transcription factor GATA4, which has previously been shown to activate a hypertrophic transcriptional program [5].

Anatomical context of Hey2

• Oscillating expression of c-Hey2 in the presomitic mesoderm suggests that the segmentation clock may use combinatorial signaling through multiple interacting bHLH factors [9].
• Transcription factor CHF1/Hey2 regulates neointimal formation in vivo and vascular smooth muscle proliferation and migration in vitro [10].
• We report the generation of transgenic mice that overexpress the transcription factor CHF1/Hey2 in the myocardium [5].
• In the developing vasculature, CHF1 first appears in the dorsal aorta at day 9.0, which precedes the reported expression of smooth muscle cell markers, and persists into adulthood [11].
• 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 [12].

Physical interactions of Hey2

• In electrophoretic mobility studies, CHF1 inhibited the binding of the ARNT/EPAS1 heterodimer to its target site [11].

Regulatory relationships of Hey2

• Co-transfection of CHF1 inhibited ARNT/EPAS1-dependent transcription by 85%, and this inhibition is dose-dependent [11].

Other interactions of Hey2

• To determine whether CHF1 might affect the function of ARNT, we performed transfection studies [11].
• In addition, hesr2 activity may be important for proper development of cardiomyocytes, thereby assuring normal left ventricular contractility [13].
• These findings reveal a ventricular myocardial cell-autonomous function for Hrt2 in the suppression of atrial cell identity and the maintenance of postnatal cardiac function [14].

Analytical, diagnostic and therapeutic context of Hey2

• 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 [15].
• 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].
• In situ hybridization analysis indicated that all hesr genes are expressed in the developing retina, but only hesr2 expression is associated spatially with gliogenesis [16].

References