Genomes and Genes
Gene Symbol: E(spl)m3-HLH
Description: Enhancer of split m3, helix-loop-helix
Alias: CG8346, Dmel\CG8346, E(Spl)-HLH-m3, E(spl)-m3, E(spl)C, E(spl)C m3, E(spl)M3, E(spl)m3, HLH-m3, HLHM3, HLHm3, bHLHc14, enhancer of split m3, helix-loop-helix, CG8346-PA, E(spl) region transcript m3, E(spl)m3-HLH-PA, enhancer of split m3, split locus enhancer protein m3
Species: fruit fly
- de Celis J, de Celis J, Ligoxygakis P, Preiss A, Delidakis C, Bray S. Functional relationships between Notch, Su(H) and the bHLH genes of the E(spl) complex: the E(spl) genes mediate only a subset of Notch activities during imaginal development. Development. 1996;122:2719-28 pubmed..Transcriptional activation mediated by Suppressor of Hairless and transcriptional repression mediated by Enhancer of split could provide greater diversity in the response of individual genes to Notch activity. ..
- Krejci A, Bray S. Notch activation stimulates transient and selective binding of Su(H)/CSL to target enhancers. Genes Dev. 2007;21:1322-7 pubmed..Unexpectedly, Su(H) occupancy was significantly and transiently increased following Notch activation, suggesting a more dynamic interaction with targets than hitherto proposed. ..
- de Celis J, Garcia Bellido A, Bray S. Activation and function of Notch at the dorsal-ventral boundary of the wing imaginal disc. Development. 1996;122:359-69 pubmed
- Schrons H, Knust E, Campos Ortega J. The Enhancer of split complex and adjacent genes in the 96F region of Drosophila melanogaster are required for segregation of neural and epidermal progenitor cells. Genetics. 1992;132:481-503 pubmed..The genes of the complex are interspersed among other genes which appear to be unrelated to the neuroepidermal lineage dichotomy. ..
- Ligoxygakis P, Bray S, Apidianakis Y, Delidakis C. Ectopic expression of individual E(spl) genes has differential effects on different cell fate decisions and underscores the biphasic requirement for notch activity in wing margin establishment in Drosophila. Development. 1999;126:2205-14 pubmed..In conclusion, E(spl) proteins have partially redundant functions, yet they have evolved distinct preferences in implementing different cell fate decisions, which closely match their individual normal expression patterns. ..
- Bardot B, Mok L, Thayer T, Ahimou F, Wesley C. The Notch amino terminus regulates protein levels and Delta-induced clustering of Drosophila Notch receptors. Exp Cell Res. 2005;304:202-23 pubmed..These observations suggest that the Notch amino terminus regulates Notch levels and clustering, which could affect the rate of Notch signaling and down-regulation. ..
- Eastman D, Slee R, Skoufos E, Bangalore L, Bray S, Delidakis C. Synergy between suppressor of Hairless and Notch in regulation of Enhancer of split m gamma and m delta expression. Mol Cell Biol. 1997;17:5620-8 pubmed..Despite the synergy observed between activated Notch and Su(H), the former affects neither the nuclear localization nor the DNA binding activity of the latter. ..
- Fay A, Misulovin Z, Li J, Schaaf C, Gause M, Gilmour D, et al. Cohesin selectively binds and regulates genes with paused RNA polymerase. Curr Biol. 2011;21:1624-34 pubmed publisher..Our findings argue that cohesin and pausing factors are recruited independently to the same genes, perhaps by GAF and the GT repeats, and that their combined action determines the level of actively elongating RNA polymerase. ..
- Lai E, Bodner R, Posakony J. The enhancer of split complex of Drosophila includes four Notch-regulated members of the bearded gene family. Development. 2000;127:3441-55 pubmed..Finally, we present our initial studies of the structure, expression and regulation of the newest member of the Brd gene family, Ocho, which is located in the recently identified Bearded Complex. ..
- Paroush Z, Finley R, Kidd T, Wainwright S, Ingham P, Brent R, et al. Groucho is required for Drosophila neurogenesis, segmentation, and sex determination and interacts directly with hairy-related bHLH proteins. Cell. 1994;79:805-15 pubmed
- Giagtzoglou N, Koumbanakis K, Fullard J, Zarifi I, Delidakis C. Role of the Sc C terminus in transcriptional activation and E(spl) repressor recruitment. J Biol Chem. 2005;280:1299-305 pubmed..In vivo, the Sc C-terminal domain is required for E(spl) recruitment in an enhancer context-dependent fashion, suggesting that in some enhancers alternative interaction surfaces can be used to recruit E(spl) proteins. ..
- Maier D, Marte B, Schafer W, Yu Y, Preiss A. Drosophila evolution challenges postulated redundancy in the E(spl) gene complex. Proc Natl Acad Sci U S A. 1993;90:5464-8 pubmed..However, we find the entire E(spl) gene complex highly conserved during Drosophila evolution, indicating that all the genes as well as their organization are of functional importance. ..
- Heitzler P, Bourouis M, Ruel L, Carteret C, Simpson P. Genes of the Enhancer of split and achaete-scute complexes are required for a regulatory loop between Notch and Delta during lateral signalling in Drosophila. Development. 1996;122:161-71 pubmed..Thus there is a regulatory loop between Notch and Delta that is under the transcriptional control of the E(spl)-C and AS-C genes. ..
- Ligoxygakis P, Yu S, Delidakis C, Baker N. A subset of notch functions during Drosophila eye development require Su(H) and the E(spl) gene complex. Development. 1998;125:2893-900 pubmed..Using misexpression experiments we also show that particular Enhancer-of-split bHLH genes can differ greatly in their contribution to lateral specification. ..
- Fisher A, Caudy M. Groucho proteins: transcriptional corepressors for specific subsets of DNA-binding transcription factors in vertebrates and invertebrates. Genes Dev. 1998;12:1931-40 pubmed
- Wurmbach E, Wech I, Preiss A. The Enhancer of split complex of Drosophila melanogaster harbors three classes of Notch responsive genes. Mech Dev. 1999;80:171-80 pubmed..The two other non-bHLH genes within the locus, m1 and m6, are unrelated to the Notch pathway: m1 might code for a protease inhibitor of the Kazal family, and m6 for a novel peptide. ..
- Duncan E, Dearden P. Evolution of a genomic regulatory domain: the role of gene co-option and gene duplication in the Enhancer of split complex. Genome Res. 2010;20:917-28 pubmed publisher..We discuss the consequence of this conserved domain for the recruitment of novel genes into the Notch signaling cascade. ..
- Maeder M, Polansky B, Robson B, EASTMAN D. Phylogenetic footprinting analysis in the upstream regulatory regions of the Drosophila enhancer of split genes. Genetics. 2007;177:1377-94 pubmed..Conserved sites provide new understandings about E(spl) regulation during development. Conserved novel sequences found upstream of multiple E(spl) genes may play a role in the expression of these genes. ..
- Mishra Gorur K, Rand M, Perez Villamil B, Artavanis Tsakonas S. Down-regulation of Delta by proteolytic processing. J Cell Biol. 2002;159:313-24 pubmed..The data support a model whereby Delta inactivation is essential for providing the critical ligand/receptor expression differential between neighboring cells in order to distinguish the signaling versus the receiving partner. ..
- Lai E, Tam B, Rubin G. Pervasive regulation of Drosophila Notch target genes by GY-box-, Brd-box-, and K-box-class microRNAs. Genes Dev. 2005;19:1067-80 pubmed..Collectively, these data establish insights into miRNA target recognition and demonstrate that the Notch signaling pathway is a major target of miRNA-mediated regulation in Drosophila. ..
- Bivik C, MacDonald R, Gunnar E, Mazouni K, Schweisguth F, Thor S. Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling. PLoS Genet. 2016;12:e1005984 pubmed publisher..These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems. ..
- Macdonald S, Pastinen T, Long A. The effect of polymorphisms in the enhancer of split gene complex on bristle number variation in a large wild-caught cohort of Drosophila melanogaster. Genetics. 2005;171:1741-56 pubmed..It may not be straightforward to extend the results of laboratory-based association studies to natural populations. ..
- Alifragis P, Poortinga G, Parkhurst S, Delidakis C. A network of interacting transcriptional regulators involved in Drosophila neural fate specification revealed by the yeast two-hybrid system. Proc Natl Acad Sci U S A. 1997;94:13099-104 pubmed..We investigated the structural requirements for some of these interactions by site-specific and deletion mutagenesis. ..
- Nagel A, Maier D, Preiss A. Su(H)-independent activity of hairless during mechano-sensory organ formation in Drosophila. Mech Dev. 2000;94:3-12 pubmed..Thereby, Hairless and numb may have partly redundant activities. This suggests that Notch-dependent binary cell fate specifications involve different sets of mediators depending on the cell type considered. ..
- Hartenstein V, Tepass U, Gruszynski deFeo E. Proneural and neurogenic genes control specification and Morphogenesis of stomatogastric nerve cell precursors in Drosophila. Dev Biol. 1996;173:213-27 pubmed
- Chanet S, Vodovar N, Mayau V, Schweisguth F. Genome engineering-based analysis of Bearded family genes reveals both functional redundancy and a nonessential function in lateral inhibition in Drosophila. Genetics. 2009;182:1101-8 pubmed publisher..We propose that inhibition of Neur-Delta interaction by Brd family members is part of the feedback loop that underlies lateral inhibition in Drosophila...
- Tapanes Castillo A, Baylies M. Notch signaling patterns Drosophila mesodermal segments by regulating the bHLH transcription factor twist. Development. 2004;131:2359-72 pubmed..Since this same cassette of Notch, Su(H) and bHLH regulators is active during vertebrate mesodermal segmentation and/or subdivision, our work suggests a conserved mechanism for Notch in early mesodermal patterning. ..
- Li X, Chen R, Zhu S. bHLH-O proteins balance the self-renewal and differentiation of Drosophila neural stem cells by regulating Earmuff expression. Dev Biol. 2017;431:239-251 pubmed publisher..Taken together, these findings reveal mechanisms underlying the regulation of the maintenance of type II NBs and differentiation of INPs through the differential expression of bHLH-O family proteins. ..
- Poortinga G, Watanabe M, Parkhurst S. Drosophila CtBP: a Hairy-interacting protein required for embryonic segmentation and hairy-mediated transcriptional repression. EMBO J. 1998;17:2067-78 pubmed..While Hairy is probably not the only segmentation gene interacting with dCtBP, we show dose-sensitive genetic interactions between dCtBP and hairy mutations. ..
- Jennings B, Pickles L, Wainwright S, Roe S, Pearl L, Ish Horowicz D. Molecular recognition of transcriptional repressor motifs by the WD domain of the Groucho/TLE corepressor. Mol Cell. 2006;22:645-55 pubmed..Our structural and functional analysis explains the rigid conservation of the WRPW motif, the sequence flexibility of eh1 motifs, and other aspects of repressor recognition by Gro in vivo. ..
- Kux K, Kiparaki M, Delidakis C. The two Tribolium E(spl) genes show evolutionarily conserved expression and function during embryonic neurogenesis. Mech Dev. 2013;130:207-25 pubmed publisher..A number of other activities have been evolutionarily conserved, most notably their ability to interact with proneural proteins Scute and Daughterless. ..
- Campos Ortega J, Knust E. Molecular analysis of a cellular decision during embryonic development of Drosophila melanogaster: epidermogenesis or neurogenesis. Eur J Biochem. 1990;190:1-10 pubmed
- Gallant P, Shiio Y, Cheng P, Parkhurst S, Eisenman R. Myc and Max homologs in Drosophila. Science. 1996;274:1523-7 pubmed..These findings indicate a potential role for Myc in germ cell development and set the stage for genetic analysis of Myc and Max. ..
- Trott R, Kalive M, Paroush Z, Bidwai A. Drosophila melanogaster casein kinase II interacts with and phosphorylates the basic helix-loop-helix proteins m5, m7, and m8 derived from the Enhancer of split complex. J Biol Chem. 2001;276:2159-67 pubmed
- Skalska L, Stojnic R, Li J, Fischer B, Cerda Moya G, Sakai H, et al. Chromatin signatures at Notch-regulated enhancers reveal large-scale changes in H3K56ac upon activation. EMBO J. 2015;34:1889-904 pubmed publisher..This intriguing example of a core histone modification increasing over short timescales may therefore underpin changes in chromatin accessibility needed to promote transcription following signalling activation. ..
- Schaaf C, Misulovin Z, Gause M, Koenig A, Dorsett D. The Drosophila enhancer of split gene complex: architecture and coordinate regulation by notch, cohesin, and polycomb group proteins. G3 (Bethesda). 2013;3:1785-94 pubmed publisher..We posit that the E(spl)-C architecture dictates where cohesin and PcG complexes bind and act when they are recruited by as yet unidentified factors, thereby controlling the E(spl)-C as a coordinated domain. ..
- Rosenberg M, Parkhurst S. Drosophila Sir2 is required for heterochromatic silencing and by euchromatic Hairy/E(Spl) bHLH repressors in segmentation and sex determination. Cell. 2002;109:447-58 pubmed..These results indicate that Sir2 in higher organisms plays an essential role in both euchromatic repression and heterochromatic silencing. ..
- Mulligan P, Yang F, Di Stefano L, Ji J, Ouyang J, Nishikawa J, et al. A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development. Mol Cell. 2011;42:689-99 pubmed publisher..These findings offer new insights into conserved mechanisms of epigenetic gene repression and regulation of development by SIRT1 in metazoans. ..
- Bang A, Bailey A, Posakony J. Hairless promotes stable commitment to the sensory organ precursor cell fate by negatively regulating the activity of the Notch signaling pathway. Dev Biol. 1995;172:479-94 pubmed
- Campos Ortega J. Genetic mechanisms of early neurogenesis in Drosophila melanogaster. J Physiol Paris. 1994;88:111-22 pubmed..The proneural genes appear to be the key elements in the regulation of the cellular decision. ..
- Wurmbach E, Preiss A. Deletion mapping in the Enhancer of split complex. Hereditas. 2014;151:159-68 pubmed publisher..Larger deletions, generated also by X-ray mutagenesis, uncover most of the E(spl)-C. The phenotypes of homozygous deficient embryos were analysed to characterize the respective loss of Notch signalling activity. ..
- Rand M, Bland C, Bond J. Methylmercury activates enhancer-of-split and bearded complex genes independent of the notch receptor. Toxicol Sci. 2008;104:163-76 pubmed publisher..MeHg transcriptional activation is partially mimicked by iodoacetamide but not by N-ethylmaleimide, two thiol-specific electrophiles, revealing a degree of specificity of cellular thiol targets in MeHg-induced transcriptional events. ..
- Lai E, Burks C, Posakony J. The K box, a conserved 3' UTR sequence motif, negatively regulates accumulation of enhancer of split complex transcripts. Development. 1998;125:4077-88 pubmed..In support of this, we present sequence analyses that implicate genes of the iroquois Complex (Iro-C) and engrailed as additional targets of K box-mediated regulation. ..
- Bartel D. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281-97 pubmed..Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes. ..
- Baker R, Kuehl J, Wilkinson G. The Enhancer of split complex arose prior to the diversification of schizophoran flies and is strongly conserved between Drosophila and stalk-eyed flies (Diopsidae). BMC Evol Biol. 2011;11:354 pubmed publisher..Results from this study provide numerous insights into the evolutionary history of the complex and will help refine the focus of studies examining the adaptive consequences of this gene expansion. ..
- Campos Ortega J. Mechanisms of early neurogenesis in Drosophila melanogaster. J Neurobiol. 1993;24:1305-27 pubmed
- Schlatter R, Maier D. The Enhancer of split and Achaete-Scute complexes of Drosophilids derived from simple ur-complexes preserved in mosquito and honeybee. BMC Evol Biol. 2005;5:67 pubmed..The ancestral ur-complexes, however, consisted most likely of just two genes: E(spl)-C contains one bHLH member of mbeta type and one Brd family member of malpha type and AS-C contains one sc/l'sc and a highly diverged ase like gene. ..
- Nellesen D, Lai E, Posakony J. Discrete enhancer elements mediate selective responsiveness of enhancer of split complex genes to common transcriptional activators. Dev Biol. 1999;213:33-53 pubmed
- Maeder M, Megley C, EASTMAN D. Differential expression of the Enhancer of split genes in the developing Drosophila midgut. Hereditas. 2009;146:11-8 pubmed publisher..These results provide further evidence that the E(spl) genes function during midgut development and that they are regulated by different factors. ..
- Leviten M, Lai E, Posakony J. The Drosophila gene Bearded encodes a novel small protein and shares 3' UTR sequence motifs with multiple Enhancer of split complex genes. Development. 1997;124:4039-51 pubmed..The deduced Brd protein shows sequence similarity to the E(spl)m4 protein, which is likewise expected to include a basic amphipathic alpha-helix, suggesting that the two proteins have related biochemical functions. ..
- Zacharioudaki E, Magadi S, Delidakis C. bHLH-O proteins are crucial for Drosophila neuroblast self-renewal and mediate Notch-induced overproliferation. Development. 2012;139:1258-69 pubmed publisher..Therefore, E(spl) and Dpn act together to maintain the NB in a self-renewing state, a process in which they are assisted by Notch, which sustains expression of the E(spl) subset. ..
- Nagel A, Apidianakis Y, Wech I, Maier D, Delidakis C, Preiss A. Neural hyperplasia induced by RNA interference with m4/malpha gene activity. Mech Dev. 2000;98:19-28 pubmed..Furthermore, a third member of the m4/malpha gene family, named bbu/tom, behaves differently with respect to RNA expression patterns, its regulation by Notch signaling and loss of function phenotypes. ..
- Macdonald S, Long A. Identifying signatures of selection at the enhancer of split neurogenic gene complex in Drosophila. Mol Biol Evol. 2005;22:607-19 pubmed publisher..All sites in regions apparently visible to various selective forces are candidates for future work to determine their phenotypic effects...
- Jennings B, Tyler D, Bray S. Target specificities of Drosophila enhancer of split basic helix-loop-helix proteins. Mol Cell Biol. 1999;19:4600-10 pubmed
- Morgenstern B, Atchley W. Evolution of bHLH transcription factors: modular evolution by domain shuffling?. Mol Biol Evol. 1999;16:1654-63 pubmed..Drawing on several lines of evidence, we suggest that modular evolution by domain shuffling may have played an important role in the evolution of this large group of transcriptional regulators. ..
- Lai E. Micro RNAs are complementary to 3' UTR sequence motifs that mediate negative post-transcriptional regulation. Nat Genet. 2002;30:363-4 pubmed..These findings suggest a more general role for micro RNAs in gene regulation through the formation of RNA duplexes. ..
- Gigliani F, Longo F, Gaddini L, Battaglia P. Interactions among the bHLH domains of the proteins encoded by the Enhancer of split and achaete-scute gene complexes of Drosophila. Mol Gen Genet. 1996;251:628-34 pubmed..Also, the pattern of interactions of the bHLH domains of certain proteins encoded by the two gene complexes may explain their functional redundancy. ..
- Secombe J, Parkhurst S. Drosophila Topors is a RING finger-containing protein that functions as a ubiquitin-protein isopeptide ligase for the hairy basic helix-loop-helix repressor protein. J Biol Chem. 2004;279:17126-33 pubmed..This work provides the first evidence that regulated proteolysis of Hairy is required for correct segmentation. ..
- Engel G, Delwig A, Rand M. The effects of methylmercury on Notch signaling during embryonic neural development in Drosophila melanogaster. Toxicol In Vitro. 2012;26:485-92 pubmed publisher..These data suggest a role for Notch signaling and the E(spl)m? target gene in MeHg toxicity, however, the site of action for E(spl)m? in this system remains to be elucidated. ..
- Lu H, Kozhina E, Mahadevaraju S, Yang D, Avila F, Erickson J. Maternal Groucho and bHLH repressors amplify the dose-sensitive X chromosome signal in Drosophila sex determination. Dev Biol. 2008;323:248-60 pubmed publisher..We present a model in which the XSE signal is amplified by a feedback mechanism that interferes with Gro-mediated repression in XX, but not XY embryos. ..