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Gene Review

E(spl)m8-HLH  -  Enhancer of split m8, helix-loop-helix

Drosophila melanogaster

Synonyms: CG8365, Dmel\CG8365, E(Spl), E(spl), E(spl) m8, ...
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High impact information on E(spl)

  • Second, the lack of N lateral signaling in these Su(H) mutant embryos was associated with a failure to express the m5 and m8 genes from the Enhancer of split Complex [E(spl)-C] [1].
  • Drosophila Groucho, like its vertebrate Transducin-like Enhancer-of-split homologues, is a corepressor that silences gene expression in numerous developmental settings [2].
  • Hairy-related proteins include the Drosophila Hairy and Enhancer of Split proteins and mammalian Hes proteins [3].
  • Indeed, loss-of-function of ed reduces the expression of the N pathway effector E(spl)m8 in proneural clusters [4].
  • Yet, the efficacy of this antagonism is quite distinct: E(spl)mbeta has the strongest vein suppression effect, whereas E(spl)m8 and E(spl)m7 are the most active bristle suppressors [5].

Biological context of E(spl)

  • The deduced protein products of m5, m7 and m8 exhibit extensive sequence homology with each other [6].
  • 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 [7].
  • In line with the prediction of a single consensus site for CKII, replacement of Ser(159) of m8 with either Ala or Asp abolishes phosphorylation, identifying this residue as the site of phosphorylation [7].
  • This gene consists of four exons, and all the introns are located within the protein-coding region at positions homologous to those of other Hes genes [8].
  • Finally, m8 genomic DNA transgenes lacking these motifs cause mild gain-of-function PNS defects and can partially phenocopy the genetic interaction of E(spl)D with Notchspl [9].

Anatomical context of E(spl)

  • Hes family of transcriptional repressors with basic Helix-loop-helix (bHLH) and Orange domains are implicated in the cell fate determination of stem cells (or precursor cells) by suppressing the expression of tissue-specific transcriptional activators [10].

Physical interactions of E(spl)

  • Using a heterologous bacterial system, we show that (i) the bHLH domains of the proteins encoded by the two gene complexes differ in their ability to form homo- and/or heterodimers; (ii) the bHLH domains of the E(spl)-C proteins m5, m7 and m8 interact with the bHLH domains of the Ac and Sc proteins [11].

Enzymatic interactions of E(spl)

  • Target genes of Notch signaling like cut and Enhancer of split m8 were suppressed by induction of Bx42 RNAi [12].

Regulatory relationships of E(spl)


Other interactions of E(spl)

  • E(spl)D, an allele of m8, encodes a truncated protein known as M8*, which, unlike wild type M8, displays exacerbated antagonism of Atonal via direct protein-protein interactions [13].
  • Lateral inhibition requires the Notch intracellular domain to coactivate Su(H)-mediated transcription of the Enhancer-of-split Complex [14].
  • Thus, by analogy to the Drosophila proteins, murine Grg proteins may interact with mammalian Hairy and E(spl) homologues (Hes proteins) and take part in a signalling pathway downstream of murine Notch [15].
  • First, K box sequences are specifically conserved in the orthologs of two structurally distinct E(spl)-C genes (m4 and m8) from a distantly related Drosophila species [9].
  • DNase I footprinting analyses show that HES-5 binds to the sequence CACNAG (called N box), a recognition sequence of Enhancer-of-split proteins [16].

Analytical, diagnostic and therapeutic context of E(spl)

  • Sequence analysis of the m8 transcription unit in the E(spl)D mutation revealed several DNA lesions [6].


  1. The neurogenic suppressor of hairless DNA-binding protein mediates the transcriptional activation of the enhancer of split complex genes triggered by Notch signaling. Lecourtois, M., Schweisguth, F. Genes Dev. (1995) [Pubmed]
  2. An eh1-like motif in odd-skipped mediates recruitment of Groucho and repression in vivo. Goldstein, R.E., Cook, O., Dinur, T., Pisanté, A., Karandikar, U.C., Bidwai, A., Paroush, Z. Mol. Cell. Biol. (2005) [Pubmed]
  3. The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain. Fisher, A.L., Ohsako, S., Caudy, M. Mol. Cell. Biol. (1996) [Pubmed]
  4. Echinoid synergizes with the Notch signaling pathway in Drosophila mesothorax bristle patterning. Escudero, L.M., Wei, S.Y., Chiu, W.H., Modolell, J., Hsu, J.C. Development (2003) [Pubmed]
  5. 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. Ligoxygakis, P., Bray, S.J., Apidianakis, Y., Delidakis, C. Development (1999) [Pubmed]
  6. Closely related transcripts encoded by the neurogenic gene complex enhancer of split of Drosophila melanogaster. Klämbt, C., Knust, E., Tietze, K., Campos-Ortega, J.A. EMBO J. (1989) [Pubmed]
  7. 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. Trott, R.L., Kalive, M., Paroush, Z., Bidwai, A.P. J. Biol. Chem. (2001) [Pubmed]
  8. Structure, chromosomal locus, and promoter of mouse Hes2 gene, a homologue of Drosophila hairy and Enhancer of split. Nishimura, M., Isaka, F., Ishibashi, M., Tomita, K., Tsuda, H., Nakanishi, S., Kageyama, R. Genomics (1998) [Pubmed]
  9. The K box, a conserved 3' UTR sequence motif, negatively regulates accumulation of enhancer of split complex transcripts. Lai, E.C., Burks, C., Posakony, J.W. Development (1998) [Pubmed]
  10. Identification and characterization of human HES2, HES3, and HES5 genes in silico. Katoh, M., Katoh, M. Int. J. Oncol. (2004) [Pubmed]
  11. Interactions among the bHLH domains of the proteins encoded by the Enhancer of split and achaete-scute gene complexes of Drosophila. Gigliani, F., Longo, F., Gaddini, L., Battaglia, P.A. Mol. Gen. Genet. (1996) [Pubmed]
  12. Inducible RNA interference uncovers the Drosophila protein Bx42 as an essential nuclear cofactor involved in Notch signal transduction. Negeri, D., Eggert, H., Gienapp, R., Saumweber, H. Mech. Dev. (2002) [Pubmed]
  13. Drosophila CK2 regulates eye morphogenesis via phosphorylation of E(spl)M8. Karandikar, U.C., Trott, R.L., Yin, J., Bishop, C.P., Bidwai, A.P. Mech. Dev. (2004) [Pubmed]
  14. Proneural enhancement by Notch overcomes Suppressor-of-Hairless repressor function in the developing Drosophila eye. Li, Y., Baker, N.E. Curr. Biol. (2001) [Pubmed]
  15. Transcripts of Grg4, a murine groucho-related gene, are detected in adjacent tissues to other murine neurogenic gene homologues during embryonic development. Koop, K.E., MacDonald, L.M., Lobe, C.G. Mech. Dev. (1996) [Pubmed]
  16. Molecular characterization of a rat negative regulator with a basic helix-loop-helix structure predominantly expressed in the developing nervous system. Akazawa, C., Sasai, Y., Nakanishi, S., Kageyama, R. J. Biol. Chem. (1992) [Pubmed]
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