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Gene Review

Hey2  -  hairy/enhancer-of-split related with YRPW...

Mus musculus

Synonyms: CHF1, Chf1, HES-related repressor protein 2, HESR-2, HRT-2, ...
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Disease relevance of Hey2


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


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].


  1. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Fischer, A., Schumacher, N., Maier, M., Sendtner, M., Gessler, M. Genes Dev. (2004) [Pubmed]
  2. Hey basic helix-loop-helix transcription factors are repressors of GATA4 and GATA6 and restrict expression of the GATA target gene ANF in fetal hearts. Fischer, A., Klattig, J., Kneitz, B., Diez, H., Maier, M., Holtmann, B., Englert, C., Gessler, M. Mol. Cell. Biol. (2005) [Pubmed]
  3. Tetralogy of fallot and other congenital heart defects in Hey2 mutant mice. Donovan, J., Kordylewska, A., Jan, Y.N., Utset, M.F. Curr. Biol. (2002) [Pubmed]
  4. Mouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in Hey2 -/- mice. Gessler, M., Knobeloch, K.P., Helisch, A., Amann, K., Schumacher, N., Rohde, E., Fischer, A., Leimeister, C. Curr. Biol. (2002) [Pubmed]
  5. Transcription factor CHF1/Hey2 suppresses cardiac hypertrophy through an inhibitory interaction with GATA4. Xiang, F., Sakata, Y., Cui, L., Youngblood, J.M., Nakagami, H., Liao, J.K., Liao, R., Chin, M.T. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  6. Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2. Sakata, Y., Kamei, C.N., Nakagami, H., Bronson, R., Liao, J.K., Chin, M.T. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  7. Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism. Kathiriya, I.S., King, I.N., Murakami, M., Nakagawa, M., Astle, J.M., Gardner, K.A., Gerard, R.D., Olson, E.N., Srivastava, D., Nakagawa, O. J. Biol. Chem. (2004) [Pubmed]
  8. Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes. Maier, M.M., Gessler, M. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  9. Oscillating expression of c-Hey2 in the presomitic mesoderm suggests that the segmentation clock may use combinatorial signaling through multiple interacting bHLH factors. Leimeister, C., Dale, K., Fischer, A., Klamt, B., Hrabe de Angelis, M., Radtke, F., McGrew, M.J., Pourquié, O., Gessler, M. Dev. Biol. (2000) [Pubmed]
  10. Transcription factor CHF1/Hey2 regulates neointimal formation in vivo and vascular smooth muscle proliferation and migration in vitro. Sakata, Y., Xiang, F., Chen, Z., Kiriyama, Y., Kamei, C.N., Simon, D.I., Chin, M.T. Arterioscler. Thromb. Vasc. Biol. (2004) [Pubmed]
  11. Cardiovascular basic helix loop helix factor 1, a novel transcriptional repressor expressed preferentially in the developing and adult cardiovascular system. Chin, M.T., Maemura, K., Fukumoto, S., Jain, M.K., Layne, M.D., Watanabe, M., Hsieh, C.M., Lee, M.E. J. Biol. Chem. (2000) [Pubmed]
  12. Hesr, a mediator of the Notch signaling, functions in heart and vessel development. Kokubo, H., Miyagawa-Tomita, S., Johnson, R.L. Trends Cardiovasc. Med. (2005) [Pubmed]
  13. Targeted disruption of hesr2 results in atrioventricular valve anomalies that lead to heart dysfunction. Kokubo, H., Miyagawa-Tomita, S., Tomimatsu, H., Nakashima, Y., Nakazawa, M., Saga, Y., Johnson, R.L. Circ. Res. (2004) [Pubmed]
  14. Essential roles of the bHLH transcription factor Hrt2 in repression of atrial gene expression and maintenance of postnatal cardiac function. Xin, M., Small, E.M., van Rooij, E., Qi, X., Richardson, J.A., Srivastava, D., Nakagawa, O., Olson, E.N. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  15. The basic helix-loop-helix genes Hesr1/Hey1 and Hesr2/Hey2 regulate maintenance of neural precursor cells in the brain. Sakamoto, M., Hirata, H., Ohtsuka, T., Bessho, Y., Kageyama, R. J. Biol. Chem. (2003) [Pubmed]
  16. The basic helix-loop-helix gene hesr2 promotes gliogenesis in mouse retina. Satow, T., Bae, S.K., Inoue, T., Inoue, C., Miyoshi, G., Tomita, K., Bessho, Y., Hashimoto, N., Kageyama, R. J. Neurosci. (2001) [Pubmed]
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