Genomes and Genes
Gene Symbol: E(spl)m4-BFM
Description: Enhancer of split m4, Bearded family member
Alias: CG6099, DmelCG6099, Dmel\CG6099, E(spl) m4, E(spl)m4, HLHm4, enhancer of split m4, bearded family member, CG6099-PA, E(spl) region transcript 4, E(spl) region transcript m4, E(spl)m4-BFM-PA, enhancer of split m4
Species: fruit fly
- 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. ..
- 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. ..
- 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. ..
- Lai E, Posakony J. Regulation of Drosophila neurogenesis by RNA:RNA duplexes?. Cell. 1998;93:1103-4 pubmed
- 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. ..
- 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. ..
- 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. ..
- 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. ..
- 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. ..
- Klämbt C, Knust E, Tietze K, Campos Ortega J. Closely related transcripts encoded by the neurogenic gene complex enhancer of split of Drosophila melanogaster. EMBO J. 1989;8:203-10 pubmed..Another lesion is a deletion in the coding region that leads to a shorter protein which, in addition, differs in its carboxy-terminal end from the wild-type protein by the presence of nine amino acids. ..
- 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. ..
- Fontana J, Posakony J. Both inhibition and activation of Notch signaling rely on a conserved Neuralized-binding motif in Bearded proteins and the Notch ligand Delta. Dev Biol. 2009;333:373-85 pubmed publisher..Our results illuminate the mechanism of an important regulatory event in Notch signaling that appears to be conserved between insects and crustaceans. ..
- Lai E, Bodner R, Kavaler J, Freschi G, Posakony J. Antagonism of notch signaling activity by members of a novel protein family encoded by the bearded and enhancer of split gene complexes. Development. 2000;127:291-306 pubmed..These results suggest that Bearded family genes encode a novel class of effectors or modulators of Notch signaling. ..
- 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
- Singson A, Leviten M, Bang A, Hua X, Posakony J. Direct downstream targets of proneural activators in the imaginal disc include genes involved in lateral inhibitory signaling. Genes Dev. 1994;8:2058-71 pubmed..Thus, one of the earliest steps in adult peripheral neurogenesis is the direct activation by proneural proteins of genes involved in restricting the expression of the SOP cell fate. ..
- 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. ..
- 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. ..
- Egger B, Gold K, Brand A. Notch regulates the switch from symmetric to asymmetric neural stem cell division in the Drosophila optic lobe. Development. 2010;137:2981-7 pubmed publisher..We show that the proneural wave transiently suppresses Notch activity in neuroepithelial cells, and that inhibition of Notch triggers the switch from symmetric, proliferative division, to asymmetric, differentiative division. ..
- 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. ..
- Rebeiz M, Castro B, Liu F, Yue F, Posakony J. Ancestral and conserved cis-regulatory architectures in developmental control genes. Dev Biol. 2012;362:282-94 pubmed publisher..We propose that these stable motif architectures have been conserved intact from a deep ancestor, in part because they mediate a special mode of regulation that cannot be supplied by the other, unstable motif instances. ..
- Baonza A, Freeman M. Control of cell proliferation in the Drosophila eye by Notch signaling. Dev Cell. 2005;8:529-39 pubmed..Delta to Notch signaling derepresses the inhibition of dE2F1 by RBF, and Delta expression depends on the secreted proteins Hedgehog and Dpp. Notch is also required for the expression of Cyclin A in the SMW. ..
- 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. ..
- 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. ..
- 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. ..
- 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
- Tseng C, Kao S, Wan C, Cho Y, Tung S, Hsu H. Notch signaling mediates the age-associated decrease in adhesion of germline stem cells to the niche. PLoS Genet. 2014;10:e1004888 pubmed publisher..Our findings expose a novel role of Notch signaling in controlling GSC-niche adhesion in response to aging, and are also of relevance to metastatic cancer cells, in which Notch signaling suppresses cell adhesion. ..
- 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. ..
- 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. ..
- Lecourtois M, Schweisguth F. The neurogenic suppressor of hairless DNA-binding protein mediates the transcriptional activation of the enhancer of split complex genes triggered by Notch signaling. Genes Dev. 1995;9:2598-608 pubmed..However, we also present evidence indicating that N signals in an Su(H)-independent manner during mesectoderm formation. ..
- Ochoa Espinosa A, Small S. Developmental mechanisms and cis-regulatory codes. Curr Opin Genet Dev. 2006;16:165-70 pubmed..They also suggest that CRMs involved in specific types of developmental events have common binding site architectures, which can be linked to their specific functions. ..
- 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. ..
- 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. ..
- 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. ..
- Lai E, Posakony J. The Bearded box, a novel 3' UTR sequence motif, mediates negative post-transcriptional regulation of Bearded and Enhancer of split Complex gene expression. Development. 1997;124:4847-56 pubmed..Finally, we show that Brd boxes and GY boxes in the E(spl)m4 gene are specifically conserved between two distantly related Drosophila species, strongly suggesting that E(spl)-C genes are regulated by these elements as well. ..
- Godt D, Schrons H, Guth S, Campos Ortega J. The distribution of transcripts of neurogenic genes in neurogenic mutants of Drosophila melanogaster. J Neurogenet. 1991;7:241-52 pubmed..We discuss these results in relation to the events of early neurogenesis. ..
- 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...
- 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. ..
- Chanet S, Schweisguth F. Regulation of epithelial polarity by the E3 ubiquitin ligase Neuralized and the Bearded inhibitors in Drosophila. Nat Cell Biol. 2012;14:467-76 pubmed publisher..This function of Neuralized was independent of its known role in Notch signalling. Thus, Neuralized has two distinct functions in epithelial cell polarity and Notch signalling. ..
- Gesellchen V, Boutros M. Managing the genome: microRNAs in Drosophila. Differentiation. 2004;72:74-80 pubmed..Many of these recent experiments provide evidence that a systematic target discovery is feasible and that the biology of miRNAs can be functionally explored using forward and reverse genetic tools. ..
- Apidianakis Y, Nagel A, Chalkiadaki A, Preiss A, Delidakis C. Overexpression of the m4 and malpha genes of the E(spl)-complex antagonizes notch mediated lateral inhibition. Mech Dev. 1999;86:39-50 pubmed..Interestingly, negative regulation of the Notch pathway by overexpression of E(spl) m4 and malpha is specific to the process of sensory organ precursor singularization and does not impinge on other instances of Notch signalling. ..
- 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...
- Zaffran S, Frasch M. Barbu: an E(spl) m4/m(alpha)-related gene that antagonizes Notch signaling and is required for the establishment of ommatidial polarity. Development. 2000;127:1115-30 pubmed
- Baker N. Notch signaling in the nervous system. Pieces still missing from the puzzle. Bioessays. 2000;22:264-73 pubmed..This review will outline the experimental evidence supporting this view of Notch signaling, and briefly evaluate some of the possible mechanisms that have been suggested. ..
- 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. ..
- Hayashi T, Xu C, Carthew R. Cell-type-specific transcription of prospero is controlled by combinatorial signaling in the Drosophila eye. Development. 2008;135:2787-96 pubmed publisher..The activity level, therefore, is dictated by the proper combination of highly cooperative selector and pre-pattern factors present in the cell...
- Bardin A, Schweisguth F. Bearded family members inhibit Neuralized-mediated endocytosis and signaling activity of Delta in Drosophila. Dev Cell. 2006;10:245-55 pubmed..We propose that inhibition of Neur by Brd proteins is important for precise spatial regulation of Dl signaling. ..
- 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