Gene Symbol: Heyl
Description: hairy/enhancer-of-split related with YRPW motif-like
Alias: Hey3, Hrt3, bHLHb33, hesr3, hairy/enhancer-of-split related with YRPW motif-like protein, HRT-3, hairy and enhance of split related 3, hairy and enhancer of split-related protein 3, hairy-related transcription factor 3, mHRT3
Species: mouse
Products:     Heyl

Top Publications

  1. Jalali A, Bassuk A, Kan L, Israsena N, Mukhopadhyay A, McGuire T, et al. HeyL promotes neuronal differentiation of neural progenitor cells. J Neurosci Res. 2011;89:299-309 pubmed publisher
    ..We found that HeyL, contrary to the classic function of Hes and Hey factors, promotes neuronal differentiation of neural progenitor ..
  2. Jeong H, Jeon U, Koo B, Kim W, Im S, Shin J, et al. Inactivation of Notch signaling in the renal collecting duct causes nephrogenic diabetes insipidus in mice. J Clin Invest. 2009;119:3290-300 pubmed publisher
  3. Hilton M, Tu X, Wu X, Bai S, Zhao H, Kobayashi T, et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med. 2008;14:306-14 pubmed publisher
    ..Thus, mesenchymal progenitors may be expanded in vitro by activating the Notch pathway, whereas bone formation in vivo may be enhanced by transiently suppressing this pathway. ..
  4. Dong Y, Jesse A, Kohn A, Gunnell L, Honjo T, Zuscik M, et al. RBPjkappa-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development. Development. 2010;137:1461-71 pubmed publisher
    ..Finally, Hes1 was identified as an RBPjkappa-dependent Notch target gene important for MPC maintenance and the suppression of in vitro chondrogenesis. ..
  5. Fukada S, Yamaguchi M, Kokubo H, Ogawa R, Uezumi A, Yoneda T, et al. Hesr1 and Hesr3 are essential to generate undifferentiated quiescent satellite cells and to maintain satellite cell numbers. Development. 2011;138:4609-19 pubmed publisher
    ..We show that Hesr1 (Hey1) and Hesr3 (Heyl) (which are known Notch target genes) are expressed simultaneously in skeletal muscle only in satellite ..
  6. Fischer A, Steidl C, Wagner T, Lang E, Jakob P, Friedl P, et al. Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition. Circ Res. 2007;100:856-63 pubmed
    ..Here we report that combined inactivation of Hey1 and HeyL, two primary target genes of Notch, causes severe heart malformations, including membranous ventricular septal ..
  7. High F, Zhang M, Proweller A, Tu L, Parmacek M, Pear W, et al. An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. J Clin Invest. 2007;117:353-63 pubmed
    ..These results provide a molecular and cellular framework for understanding the role of Notch signaling in the etiology of congenital heart disease. ..
  8. Fischer A, Klattig J, Kneitz B, Diez H, Maier M, Holtmann B, et al. 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. Mol Cell Biol. 2005;25:8960-70 pubmed
    ..In addition, the promoter activity of the GATA4/6 target gene ANF was inhibited by Hey1, Hey2, and HeyL. Protein interaction and mutation analyses suggest that repression is due to direct binding of Hey proteins to ..
  9. Schuster Gossler K, Cordes R, Müller J, Geffers I, Delany Heiken P, Taft M, et al. Context-Dependent Sensitivity to Mutations Disrupting the Structural Integrity of Individual EGF Repeats in the Mouse Notch Ligand DLL1. Genetics. 2016;202:1119-33 pubmed publisher
    ..In conclusion, the structural integrity of each individual EGF repeat in the extracellular domain of DLL1 is necessary for full DLL1 activity, and certain mutations in Dll1 might contribute to spondylocostal dysostosis in humans. ..

More Information


  1. Schuster Gossler K, Cordes R, Gossler A. Premature myogenic differentiation and depletion of progenitor cells cause severe muscle hypotrophy in Delta1 mutants. Proc Natl Acad Sci U S A. 2007;104:537-42 pubmed
  2. Tateya T, Imayoshi I, Tateya I, Ito J, Kageyama R. Cooperative functions of Hes/Hey genes in auditory hair cell and supporting cell development. Dev Biol. 2011;352:329-40 pubmed publisher
  3. Moran T, Goldberg L, Serviss S, Raetzman L. Numb deletion in POMC-expressing cells impairs pituitary intermediate lobe cell adhesion, progenitor cell localization, and neuro-intermediate lobe boundary formation. Mol Endocrinol. 2011;25:117-27 pubmed publisher
    ..Unexpectedly, Notch activity appears normal in conditional knockout mice. Thus, Numb is critical for maintaining cell-cell interactions in the pituitary intermediate lobe that are essential for proper cell placement. ..
  4. Jory A, Le Roux I, Gayraud Morel B, Rocheteau P, Cohen Tannoudji M, Cumano A, et al. Numb promotes an increase in skeletal muscle progenitor cells in the embryonic somite. Stem Cells. 2009;27:2769-80 pubmed publisher
    ..Thus, we propose that Numb can regulate the self-renewal of dermal and muscle progenitors during a lineage progression. ..
  5. Mukhopadhyay A, Jarrett J, Chlon T, Kessler J. HeyL regulates the number of TrkC neurons in dorsal root ganglia. Dev Biol. 2009;334:142-51 pubmed publisher
    The basic-helix-loop-helix transcription factor HeyL is expressed at high levels by neural crest progenitor cells (NCPs) that give rise to neurons and glia in dorsal root ganglia (DRG)...
  6. Chen L, Al Awqati Q. Segmental expression of Notch and Hairy genes in nephrogenesis. Am J Physiol Renal Physiol. 2005;288:F939-52 pubmed
    ..We found that among all of Notch downstream Hairy genes, only Hes1, Hes5, Hey1, and HeyL were expressed in a segment-specific manner in early nephrons and their expression pattern changed dynamically ..
  7. Rowton M, Ramos P, Anderson D, Rhee J, Cunliffe H, Rawls A. Regulation of mesenchymal-to-epithelial transition by PARAXIS during somitogenesis. Dev Dyn. 2013;242:1332-44 pubmed publisher
    ..These data demonstrate that PARAXIS initiates and stabilizes somite epithelialization by integrating signals from multiple pathways to control the reorganization of the ECM, cytoskeleton, and adhesion junctions during MET. ..
  8. Heisig J, Weber D, Englberger E, Winkler A, Kneitz S, Sung W, et al. Target gene analysis by microarrays and chromatin immunoprecipitation identifies HEY proteins as highly redundant bHLH repressors. PLoS Genet. 2012;8:e1002728 pubmed publisher
    ..The striking overlap of cardiac defects in HEY2 and combined HEY1/HEYL knockout mice suggested that all three HEY genes fulfill overlapping function in target cells...
  9. Oyama T, Harigaya K, Sasaki N, Okamura Y, Kokubo H, Saga Y, et al. Mastermind-like 1 (MamL1) and mastermind-like 3 (MamL3) are essential for Notch signaling in vivo. Development. 2011;138:5235-46 pubmed publisher
    ..These results indicate that engagement of Mam is essential for Notch signaling, and that the three Mam isoforms have distinct roles in vivo. ..
  10. Raft S, Andrade L, Shao D, Akiyama H, Henkemeyer M, Wu D. Ephrin-B2 governs morphogenesis of endolymphatic sac and duct epithelia in the mouse inner ear. Dev Biol. 2014;390:51-67 pubmed publisher
    ..We propose that developmental dysplasias described here are a gene dose-sensitive cause of the vestibular dysfunction observed in EphB-Efnb2 signaling-deficient mice. ..
  11. Lee S, Lee S, Yang H, Song S, Kim K, Saunders T, et al. Notch pathway targets proangiogenic regulator Sox17 to restrict angiogenesis. Circ Res. 2014;115:215-26 pubmed publisher
    ..Our findings demonstrate that the Notch pathway restricts sprouting angiogenesis by reducing the expression of proangiogenic regulator Sox17. ..
  12. Stafford D, Dichmann D, Chang J, Harland R. Deletion of the sclerotome-enriched lncRNA PEAT augments ribosomal protein expression. Proc Natl Acad Sci U S A. 2017;114:101-106 pubmed publisher
    ..RNA-seq on PEAT mutant embryos showed that loss of PEAT modestly increases bone morphogenetic protein target gene expression and also elevates the expression of a large subset of ribosomal protein mRNAs. ..
  13. Leimeister C, Schumacher N, Steidl C, Gessler M. Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos. Mech Dev. 2000;98:175-8 pubmed
    ..Here we report the embryonic expression of the hairy-related basic helix-loop-helix gene HeyL in wild-type and Notch pathway mutant mice...
  14. Aujla P, Naratadam G, Xu L, Raetzman L. Notch/Rbpj? signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons. Development. 2013;140:3511-21 pubmed publisher
    ..Taken together, our results demonstrate that Notch/Rbpj? signaling regulates the generation and differentiation of Arc neurons, which contribute to homeostatic regulation of body size. ..
  15. Tsunematsu R, Nakayama K, Oike Y, Nishiyama M, Ishida N, Hatakeyama S, et al. Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development. J Biol Chem. 2004;279:9417-23 pubmed
    ..Expression of Notch1, -2, or -3 or of cyclin E was unaffected in Fbw7(-/-) embryos. Mammalian Fbw7 thus appears to play an indispensable role in negative regulation of the Notch4-Hey1 pathway and is required for vascular development. ..
  16. Golson M, Le Lay J, Gao N, Brämswig N, Loomes K, Oakey R, et al. Jagged1 is a competitive inhibitor of Notch signaling in the embryonic pancreas. Mech Dev. 2009;126:687-99 pubmed publisher
    ..Expression of the Notch modifier Manic Fringe (Mfng) is limited to endocrine precursors, providing a possible explanation for the inhibition of Notch signaling by Jag1 during mid-gestation embryonic pancreas development. ..
  17. Satow T, Bae S, Inoue T, Inoue C, Miyoshi G, Tomita K, et al. The basic helix-loop-helix gene hesr2 promotes gliogenesis in mouse retina. J Neurosci. 2001;21:1265-73 pubmed
    ..Interestingly, hesr2 but not hesr1 or hesr3 promoted gliogenesis while inhibiting rod genesis without affecting cell proliferation or death, suggesting that ..
  18. Di Giovanni V, Walker K, Bushnell D, Schaefer C, Sims Lucas S, Puri P, et al. Fibroblast growth factor receptor-Frs2α signaling is critical for nephron progenitors. Dev Biol. 2015;400:82-93 pubmed publisher
    ..Thus, Fgfr1 and Fgfr2 have synergistic roles in maintaining nephron progenitors; furthermore, Fgfr signaling in nephron progenitors appears to be mediated predominantly by Frs2α. ..
  19. Copeland J, Feng Y, Neradugomma N, Fields P, Vivian J. Notch signaling regulates remodeling and vessel diameter in the extraembryonic yolk sac. BMC Dev Biol. 2011;11:12 pubmed publisher
    ..We propose a role for Notch signaling in elaborating the microenvironment of the nascent arteriole, suggesting novel regulatory connections between Notch signaling and other signaling pathways during endothelial differentiation. ..
  20. Nakagawa O, Nakagawa M, Richardson J, Olson E, Srivastava D. HRT1, HRT2, and HRT3: a new subclass of bHLH transcription factors marking specific cardiac, somitic, and pharyngeal arch segments. Dev Biol. 1999;216:72-84 pubmed
    ..Here, we describe a new subclass of bHLH proteins, HRT1 (Hairy-related transcription factor 1), HRT2, and HRT3, that share high homology with the Hairy family of proteins yet have characteristics that are distinct from those ..
  21. Firulli B, Hadzic D, McDaid J, Firulli A. The basic helix-loop-helix transcription factors dHAND and eHAND exhibit dimerization characteristics that suggest complex regulation of function. J Biol Chem. 2000;275:33567-73 pubmed
    ..Taken together, these results show that dHAND and eHAND can form homo- and heterodimer combinations with multiple bHLH partners and that this broad dimerization profile reflects the mechanisms by which HAND genes regulate transcription. ..
  22. Nakagawa O, McFadden D, Nakagawa M, Yanagisawa H, Hu T, Srivastava D, et al. Members of the HRT family of basic helix-loop-helix proteins act as transcriptional repressors downstream of Notch signaling. Proc Natl Acad Sci U S A. 2000;97:13655-60 pubmed
    ..These findings identify HRT genes as downstream targets for Notch signaling and reveal a negative autoregulatory loop whereby HRT proteins repress their own expression through interference with Notch signaling. ..
  23. Kanno K, Ishiura S. Differential effects of the HESR/HEY transcription factor family on dopamine transporter reporter gene expression via variable number of tandem repeats. J Neurosci Res. 2011;89:562-75 pubmed publisher
    ..Other members of the HESR (HEY) family, including HESR2 (HEY2) and 3 (HEYL), have similar DNA-binding domains...
  24. Sugita S, Hosaka Y, Okada K, Mori D, Yano F, Kobayashi H, et al. Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2. Proc Natl Acad Sci U S A. 2015;112:3080-5 pubmed publisher
    ..Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders. ..
  25. Garcia T, Farmaha J, Kow S, Hofmann M. RBPJ in mouse Sertoli cells is required for proper regulation of the testis stem cell niche. Development. 2014;141:4468-78 pubmed publisher
  26. Luxan G, Casanova J, Martínez Poveda B, Prados B, D Amato G, MacGrogan D, et al. Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy. Nat Med. 2013;19:193-201 pubmed publisher
    ..These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction. ..
  27. Onishi M, Yasunaga T, Tanaka H, Nishimune Y, Nozaki M. Gene structure and evolution of testicular haploid germ cell-specific genes, Oxct2a and Oxct2b. Genomics. 2004;83:647-57 pubmed
    ..Dot matrix and phylogenetic tree analyses demonstrated that multiple rounds of intrachromosomal gene conversion between the two loci occurred in each species independently. ..
  28. Hayashi T, Kokubo H, Hartman B, Ray C, Reh T, Bermingham McDonogh O. Hesr1 and Hesr2 may act as early effectors of Notch signaling in the developing cochlea. Dev Biol. 2008;316:87-99 pubmed publisher
    ..This treatment also reduces Hesr1 and Hesr2 expression by as much as 80%. These results support the hypothesis that Hesr1 and Hesr2 are the downstream mediators of the prosensory function of Notch in early cochlear development. ..
  29. Im S, Jeong H, Jeong H, Kim K, Hwang D, Ikegami M, et al. Disruption of sorting nexin 5 causes respiratory failure associated with undifferentiated alveolar epithelial type I cells in mice. PLoS ONE. 2013;8:e58511 pubmed publisher
    ..These results demonstrate that Snx5 is necessary for the differentiation of alveolar epithelial type I cells, which may underlie the adaptation to air breathing at birth...
  30. Nunes A, Wuebbles R, Sarathy A, Fontelonga T, Deries M, Burkin D, et al. Impaired fetal muscle development and JAK-STAT activation mark disease onset and progression in a mouse model for merosin-deficient congenital muscular dystrophy. Hum Mol Genet. 2017;26:2018-2033 pubmed publisher
    ..Our data reveal for the first time that dyW-/- mice exhibit a myogenesis defect already in utero. We propose that overactivation of JAK-STAT signaling is part of the mechanism underlying disease onset and progression in dyW-/- mice. ..
  31. Canalis E, Zanotti S. Hairy and Enhancer of Split-Related With YRPW Motif-Like (HeyL) Is Dispensable for Bone Remodeling in Mice. J Cell Biochem. 2017;118:1819-1826 pubmed publisher
    Notch induces Hairy Enhancer of Split (Hes)1 and Hes-related with YRPW motif (Hey) Hey1, Hey2 and Hey-like (HeyL) expression in osteoblasts, but it is not known whether any of these target genes mediates the effect of Notch in the ..
  32. Leimeister C, Externbrink A, Klamt B, Gessler M. Hey genes: a novel subfamily of hairy- and Enhancer of split related genes specifically expressed during mouse embryogenesis. Mech Dev. 1999;85:173-7 pubmed
    ..The diversity of expression patterns implies unique functions in neurogenesis, somitogenesis and organogenesis. ..
  33. Han L, Diehl A, Nguyen N, Korangath P, Teo W, Cho S, et al. The Notch pathway inhibits TGFβ signaling in breast cancer through HEYL-mediated crosstalk. Cancer Res. 2014;74:6509-18 pubmed publisher
    ..Here, we present evidence of crosstalk between these two pathways through HEYL. HEYL, a basic helix-loop-helix transcription factor and a direct target of Notch signaling, is specifically ..
  34. Liu Z, Tan Y, Beecham G, Seo D, Tian R, Li Y, et al. Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis. Atherosclerosis. 2012;225:296-303 pubmed publisher
    ..Notch signaling may be linked to human CAD risk. These findings implicate a potential involvement of Notch signaling in atherosclerosis. ..
  35. Garcia M, Ghiani M, Lefort A, Libert F, Strollo S, Vassart G. LGR5 deficiency deregulates Wnt signaling and leads to precocious Paneth cell differentiation in the fetal intestine. Dev Biol. 2009;331:58-67 pubmed publisher
    ..Together, our data identify LGR5 as a negative regulator of the Wnt pathway in the developing intestine. ..
  36. Leimeister C, Schumacher N, Gessler M. Expression of Notch pathway genes in the embryonic mouse metanephros suggests a role in proximal tubule development. Gene Expr Patterns. 2003;3:595-8 pubmed
    ..Our results point to a Lfng-dependent role for Notch signalling in the development of nephron segments, especially the proximal tubules. ..
  37. Kusumi K, Mimoto M, Covello K, Beddington R, Krumlauf R, Dunwoodie S. Dll3 pudgy mutation differentially disrupts dynamic expression of somite genes. Genesis. 2004;39:115-21 pubmed
    ..the Dll3(pu) mutation has different effects on the expression of cycling (Lfng and Hes7) and stage-specific genes (Hey3 and Mesp2)...
  38. Tu X, Chen J, Lim J, Karner C, Lee S, Heisig J, et al. Physiological notch signaling maintains bone homeostasis via RBPjk and Hey upstream of NFATc1. PLoS Genet. 2012;8:e1002577 pubmed publisher
    ..Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass...
  39. Steidl C, Leimeister C, Klamt B, Maier M, Nanda I, Dixon M, et al. Characterization of the human and mouse HEY1, HEY2, and HEYL genes: cloning, mapping, and mutation screening of a new bHLH gene family. Genomics. 2000;66:195-203 pubmed
    ..factor genes from mouse and human (hairy and Enhancer-of-split related with YRPW motif; HEY1, HEY2, and HEYL). All three HEY genes have a similar genomic structure with five exons...
  40. Schuster Gossler K, Harris B, Johnson K, Serth J, Gossler A. Notch signalling in the paraxial mesoderm is most sensitive to reduced Pofut1 levels during early mouse development. BMC Dev Biol. 2009;9:6 pubmed publisher
    ..Reduced POFUT1 levels might affect Notch trafficking or overall O-fucosylation. Alternatively, reduced O-fucosylation might preferentially affect sites that are substrates for LFNG and thus important for somite formation and patterning. ..
  41. Goldberg L, Aujla P, Raetzman L. Persistent expression of activated Notch inhibits corticotrope and melanotrope differentiation and results in dysfunction of the HPA axis. Dev Biol. 2011;358:23-32 pubmed publisher
    ..Taken together, these findings show that Notch signaling is sufficient to prevent corticotrope and melanotrope differentiation, resulting in dysregulation of the HPA axis. ..
  42. Mommersteeg M, Yeh M, Parnavelas J, Andrews W. Disrupted Slit-Robo signalling results in membranous ventricular septum defects and bicuspid aortic valves. Cardiovasc Res. 2015;106:55-66 pubmed publisher
  43. Yi L, Domyan E, Lewandoski M, Sun X. Fibroblast growth factor 9 signaling inhibits airway smooth muscle differentiation in mouse lung. Dev Dyn. 2009;238:123-37 pubmed publisher
    ..This model also represents our findings on the genetic relationship between FGF9 and sonic hedgehog (SHH) in the establishment of airway SMC pattern. ..