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Gene Review

N  -  Notch

Drosophila melanogaster

Synonyms: 1.1, 16-178, 16-55, Ax, CG3936, ...
 
 
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Disease relevance of N

  • The Notch family of transmembrane receptor proteins mediate developmental cell-fate decisions, and mutations in mammalian Notch genes have been implicated in leukaemia, breast cancer, stroke and dementia [1].
  • Loss of genes of the Notch signaling pathway results in a neurogenic phenotype: hyperplasia of the nervous system accompanied by a parallel loss of epidermis [2].
  • Serrate-Notch signaling defines the scope of the initial denticle field by modulating EGFR activation [3].
  • These Notch proteins not only suppress the neural hypertrophy observed in Notch- embryos, but also generate a phenotype in which elements of the embryonic nervous system are underproduced [4].
  • Wasp, the Drosophila Wiskott-Aldrich syndrome gene homologue, is required for cell fate decisions mediated by Notch signaling [5].
 

Psychiatry related information on N

  • Transmembrane cleavage of Notch is essential for signal transduction, and transmembrane cleavage of beta-APP generates pathogenic amyloid peptides implicated in Alzheimer's disease [6].
  • Here we demonstrate that Notch loss of function produces memory deficits in Drosophila melanogaster [7].
  • Proneural gene self-stimulation in neural precursors: an essential mechanism for sense organ development that is regulated by Notch signaling [8].
  • Here we show that lgd is required in all imaginal disc cells to suppress the activity of the Notch pathway. lgd encodes a member of a poorly characterized protein family present in all animals, which includes a member that is involved in an inheritable form of mental retardation in humans [9].
 

High impact information on N

  • Antagonism between the EGF-receptor (EGFR) and Notch pathways in particular is well documented, although the underlying mechanism is poorly understood [10].
  • We show that trafficking of the Notch ligand Delta is different in the two daughter cells [11].
  • Here we identify a new mechanism for disrupting Notch signaling in human tumorigenesis, characterized by altered function of a new ortholog of the Drosophila melanogaster Notch co-activator molecule Mastermind [12].
  • The transcription of Ofut1 is developmentally regulated, and surprisingly, overexpression of Ofut1 inhibits Notch signaling [13].
  • Recent studies in vertebrates and Drosophila melanogaster have revealed that Fringe-mediated activation of the Notch pathway has a role in patterning cell layers during organogenesis [14].
 

Biological context of N

  • Retinal morphogenesis is organized by Notch signaling at the dorsoventral (DV) boundary in the DP [15].
  • Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing [16].
  • Delta and Serrate are redundant Notch ligands required for asymmetric cell divisions within the Drosophila sensory organ lineage [17].
  • Here, we show that Notch, a transmembrane receptor mediated cell-cell communication, functions as a binary switch in cell fate specification during asymmetric divisions of the SOP and its daughter cells in embryogenesis [18].
  • The enhancer of split complex of Drosophila includes four Notch-regulated members of the bearded gene family [19].
 

Anatomical context of N

  • Previous work has shown that the Notch signalling pathway also has a proneural role in the eye (as well as a later, opposite function when it restricts the number of cells becoming photoreceptors - a process of lateral inhibition) [20].
  • The daughterless gene functions together with Notch and Delta in the control of ovarian follicle development in Drosophila [21].
  • Instead, we show that Su(dx) regulates the postendocytic sorting of Notch within the early endosome to an Hrs- and ubiquitin-enriched subdomain en route to the late endosome [22].
  • We rule out models by which Su(dx) downregulates Notch through modulating Deltex or by limiting the adherens junction accumulation of Notch [22].
  • Reciprocal regulatory interactions between the Notch and Ras signaling pathways in the Drosophila embryonic mesoderm [23].
 

Associations of N with chemical compounds

 

Physical interactions of N

  • Abruptex[M1] showed less activity than wild-type Notch in its ability to bind Delta and Serrate and was expressed at reduced levels on the cell surface [29].
  • Thus, inhibition of Notch-Serrate binding by O-fucosylation of EGF12 might be needed in certain contexts to allow efficient Notch signaling [30].
  • We also find that the Hairless protein interacts with Notch signalling during wing development and inhibits the activity of Su(H) [31].
  • RESULTS: We used the Drosophila system to show that Notch is ubiquitinated and destabilized by Nedd4 in a manner requiring the PPSY motif in the Notch intracellular domain [28].
  • In the NB4-2->GMC-1->RP2/sib lineage, one of the well-studied neuronal lineages in the ventral nerve cord, the Notch (N) signaling interacts with the asymmetrically localized Numb (Nb) to specify sibling neuronal fates to daughter cells of GMC-1 [32].
 

Enzymatic interactions of N

  • Notch gain-of-function alleles in which Notch activity is not restricted to the dorsoventral boundary cause miss-expression of cut and wingless and overgrowth of the disc, illustrating the importance of localised Notch activation for wing development [33].
  • By using an enhancer for the Notch target gene Enhancer of split mdelta, we show that Notch becomes activated specifically in R4 [34].
  • Target genes of Notch signaling like cut and Enhancer of split m8 were suppressed by induction of Bx42 RNAi [35].
  • Notch and the m9/10 gene (groucho) of the Enhancer of split (E(spI)) complex are members of the "Notch group" of genes, which is required for a variety of cell fate choices in Drosophila [36].
  • We suggest that the Notch pathway bifurcates after the activation of Suppressor of Hairless and that Enhancer of split activity is not required when the consequence of Notch function is the transcriptional activation of downstream genes [37].
 

Regulatory relationships of N

  • Unidirectional signaling from cells expressing Delta (Dl) to cells expressing Notch is a key feature of many developmental processes [38].
  • Loss of ed suppresses the loss of neuronal elements caused by ectopic activation of the Notch signaling pathway [2].
  • Scabrous and Gp150 are endosomal proteins that regulate Notch activity [39].
  • During wing development in Drosophila, Wingless (Wg) is activated by Notch signaling along the dorsal-ventral boundary of the wing imaginal disc and acts as a morphogen to organize gene expression and cell growth [40].
  • Serrate accomplishes this task by activating Notch in a discrete domain, the main purpose of which is to broaden the spatially regulated expression of Rhomboid [3].
 

Other interactions of N

  • During wing development in Drosophila, the Notch receptor is activated along the border between dorsal and ventral cells, leading to the specification of specialized cells that express Wingless (Wg) and organize wing growth and patterning [1].
  • The DNA-binding transcription factor Suppressor of Hairless [Su(H)] functions as an activator during Notch (N) pathway signaling, but can act as a repressor in the absence of signaling [41].
  • Neuralized is essential for a subset of Notch pathway-dependent cell fate decisions during Drosophila eye development [42].
  • We provide evidence that Notch activation by its ligand Delta is the second Hh-dependent signal required for neural determination [20].
  • These phenotypes suggest a functional relation between ed and the Notch (N) pathway [43].
  • These observations argue against models in which Fringe-dependent glycosylation modulates Notch signaling by acting as a precursor to subsequent modifications and instead establish the simple addition of N-acetylglucosamine as a basis for the effects of Fringe on Drosophila Notch-ligand binding [44].
 

Analytical, diagnostic and therapeutic context of N

  • The basis for the genetic antimorphism of NM1 seems to reside in the titration of Notch wild-type products into NM1/N+ nonfunctional dimers and/or the titration of Delta products into nonfunctional ligand-receptor complexes [45].
  • Kul cleaves Dl efficiently both in cell culture and in flies, and has previously been shown not to be necessary for Notch processing during signaling [38].
  • Molecularly, Hairless inhibits Notch target gene activation by directly binding to the Notch signal transducer Su(H) [46].
  • To elucidate the roles of l-Fng in vertebrate neurogenesis, we transfected chick l-Fng (C-l-Fng) to chick neural tube using the in ovo electroporation technique and examined the subsequent changes in expression of Notch-related genes [47].
  • Various kinds of data, in particular from cell transplantation studies and from genetic and molecular analyses, suggest that the proteins encoded by the genes Notch and Delta interact at the membrane of the neuroectodermal cells to provide a regulatory signal [48].

References

  1. Fringe modulates Notch-ligand interactions. Panin, V.M., Papayannopoulos, V., Wilson, R., Irvine, K.D. Nature (1997) [Pubmed]
  2. Echinoid mutants exhibit neurogenic phenotypes and show synergistic interactions with the Notch signaling pathway. Ahmed, A., Chandra, S., Magarinos, M., Vaessin, H. Development (2003) [Pubmed]
  3. Serrate-Notch signaling defines the scope of the initial denticle field by modulating EGFR activation. Walters, J.W., Muñoz, C., Paaby, A.B., Dinardo, S. Dev. Biol. (2005) [Pubmed]
  4. Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei. Lieber, T., Kidd, S., Alcamo, E., Corbin, V., Young, M.W. Genes Dev. (1993) [Pubmed]
  5. Wasp, the Drosophila Wiskott-Aldrich syndrome gene homologue, is required for cell fate decisions mediated by Notch signaling. Ben-Yaacov, S., Le Borgne , R., Abramson, I., Schweisguth, F., Schejter, E.D. J. Cell Biol. (2001) [Pubmed]
  6. Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila. Chung, H.M., Struhl, G. Nat. Cell Biol. (2001) [Pubmed]
  7. Notch is required for long-term memory in Drosophila. Presente, A., Boyles, R.S., Serway, C.N., de Belle, J.S., Andres, A.J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  8. Proneural gene self-stimulation in neural precursors: an essential mechanism for sense organ development that is regulated by Notch signaling. Culí, J., Modolell, J. Genes Dev. (1998) [Pubmed]
  9. The Drosophila Notch Inhibitor and Tumor Suppressor Gene lethal (2) giant discs Encodes a Conserved Regulator of Endosomal Trafficking. Jaekel, R., Klein, T. Dev. Cell (2006) [Pubmed]
  10. EGFR signaling attenuates Groucho-dependent repression to antagonize Notch transcriptional output. Hasson, P., Egoz, N., Winkler, C., Volohonsky, G., Jia, S., Dinur, T., Volk, T., Courey, A.J., Paroush, Z. Nat. Genet. (2005) [Pubmed]
  11. Asymmetric Rab 11 endosomes regulate delta recycling and specify cell fate in the Drosophila nervous system. Emery, G., Hutterer, A., Berdnik, D., Mayer, B., Wirtz-Peitz, F., Gaitan, M.G., Knoblich, J.A. Cell (2005) [Pubmed]
  12. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Tonon, G., Modi, S., Wu, L., Kubo, A., Coxon, A.B., Komiya, T., O'Neil, K., Stover, K., El-Naggar, A., Griffin, J.D., Kirsch, I.R., Kaye, F.J. Nat. Genet. (2003) [Pubmed]
  13. Regulation of notch signaling by o-linked fucose. Okajima, T., Irvine, K.D. Cell (2002) [Pubmed]
  14. The homeobox gene mirror links EGF signalling to embryonic dorso-ventral axis formation through notch activation. Jordan, K.C., Clegg, N.J., Blasi, J.A., Morimoto, A.M., Sen, J., Stein, D., McNeill, H., Deng, W.M., Tworoger, M., Ruohola-Baker, H. Nat. Genet. (2000) [Pubmed]
  15. Novel signaling from the peripodial membrane is essential for eye disc patterning in Drosophila. Cho, K.O., Chern, J., Izaddoost, S., Choi, K.W. Cell (2000) [Pubmed]
  16. Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing. Johnston, L.A., Edgar, B.A. Nature (1998) [Pubmed]
  17. Delta and Serrate are redundant Notch ligands required for asymmetric cell divisions within the Drosophila sensory organ lineage. Zeng, C., Younger-Shepherd, S., Jan, L.Y., Jan, Y.N. Genes Dev. (1998) [Pubmed]
  18. Control of daughter cell fates during asymmetric division: interaction of Numb and Notch. Guo, M., Jan, L.Y., Jan, Y.N. Neuron (1996) [Pubmed]
  19. The enhancer of split complex of Drosophila includes four Notch-regulated members of the bearded gene family. Lai, E.C., Bodner, R., Posakony, J.W. Development (2000) [Pubmed]
  20. Notch signalling and the initiation of neural development in the Drosophila eye. Baonza, A., Freeman, M. Development (2001) [Pubmed]
  21. The daughterless gene functions together with Notch and Delta in the control of ovarian follicle development in Drosophila. Cummings, C.A., Cronmiller, C. Development (1994) [Pubmed]
  22. Regulation of notch endosomal sorting and signaling by Drosophila Nedd4 family proteins. Wilkin, M.B., Carbery, A.M., Fostier, M., Aslam, H., Mazaleyrat, S.L., Higgs, J., Myat, A., Evans, D.A., Cornell, M., Baron, M. Curr. Biol. (2004) [Pubmed]
  23. Reciprocal regulatory interactions between the Notch and Ras signaling pathways in the Drosophila embryonic mesoderm. Carmena, A., Buff, E., Halfon, M.S., Gisselbrecht, S., Jiménez, F., Baylies, M.K., Michelson, A.M. Dev. Biol. (2002) [Pubmed]
  24. Expression and function of decapentaplegic and thick veins during the differentiation of the veins in the Drosophila wing. de Celis, J.F. Development (1997) [Pubmed]
  25. Notch pathway repression by vestigial is required to promote indirect flight muscle differentiation in Drosophila melanogaster. Bernard, F., Dutriaux, A., Silber, J., Lalouette, A. Dev. Biol. (2006) [Pubmed]
  26. Drosophila Gp150 is required for early ommatidial development through modulation of Notch signaling. Fetchko, M., Huang, W., Li, Y., Lai, Z.C. EMBO J. (2002) [Pubmed]
  27. Notch-induced proteolysis and nuclear localization of the Delta ligand. Bland, C.E., Kimberly, P., Rand, M.D. J. Biol. Chem. (2003) [Pubmed]
  28. Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation. Sakata, T., Sakaguchi, H., Tsuda, L., Higashitani, A., Aigaki, T., Matsuno, K., Hayashi, S. Curr. Biol. (2004) [Pubmed]
  29. Ligand-binding and signaling properties of the Ax[M1] form of Notch. Pérez, L., Milán, M., Bray, S., Cohen, S.M. Mech. Dev. (2005) [Pubmed]
  30. An O-fucose site in the ligand binding domain inhibits Notch activation. Lei, L., Xu, A., Panin, V.M., Irvine, K.D. Development (2003) [Pubmed]
  31. Two different activities of Suppressor of Hairless during wing development in Drosophila. Klein, T., Seugnet, L., Haenlin, M., Martinez Arias, A. Development (2000) [Pubmed]
  32. Cell division genes promote asymmetric interaction between Numb and Notch in the Drosophila CNS. Wai, P., Truong, B., Bhat, K.M. Development (1999) [Pubmed]
  33. Activation and function of Notch at the dorsal-ventral boundary of the wing imaginal disc. de Celis, J.F., Garcia-Bellido, A., Bray, S.J. Development (1996) [Pubmed]
  34. Frizzled regulation of Notch signalling polarizes cell fate in the Drosophila eye. Cooper, M.T., Bray, S.J. Nature (1999) [Pubmed]
  35. 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]
  36. Human homologs of a Drosophila Enhancer of split gene product define a novel family of nuclear proteins. Stifani, S., Blaumueller, C.M., Redhead, N.J., Hill, R.E., Artavanis-Tsakonas, S. Nat. Genet. (1992) [Pubmed]
  37. 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. de Celis, J.F., de Celis, J., Ligoxygakis, P., Preiss, A., Delidakis, C., Bray, S. Development (1996) [Pubmed]
  38. Unidirectional Notch signaling depends on continuous cleavage of Delta. Sapir, A., Assa-Kunik, E., Tsruya, R., Schejter, E., Shilo, B.Z. Development (2005) [Pubmed]
  39. Scabrous and Gp150 are endosomal proteins that regulate Notch activity. Li, Y., Fetchko, M., Lai, Z.C., Baker, N.E. Development (2003) [Pubmed]
  40. Refinement of wingless expression by a wingless- and notch-responsive homeodomain protein, defective proventriculus. Nakagoshi, H., Shirai, T., Nabeshima, Y., Matsuzaki, F. Dev. Biol. (2002) [Pubmed]
  41. Default repression and Notch signaling: Hairless acts as an adaptor to recruit the corepressors Groucho and dCtBP to Suppressor of Hairless. Barolo, S., Stone, T., Bang, A.G., Posakony, J.W. Genes Dev. (2002) [Pubmed]
  42. Neuralized is essential for a subset of Notch pathway-dependent cell fate decisions during Drosophila eye development. Lai, E.C., Rubin, G.M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  43. 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]
  44. In vitro reconstitution of the modulation of Drosophila Notch-ligand binding by Fringe. Xu, A., Haines, N., Dlugosz, M., Rana, N.A., Takeuchi, H., Haltiwanger, R.S., Irvine, K.D. J. Biol. Chem. (2007) [Pubmed]
  45. Genetic and molecular characterization of a Notch mutation in its Delta- and Serrate-binding domain in Drosophila. de Celis, J.F., Barrio, R., del Arco, A., García-Bellido, A. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  46. Genetic screen for modifiers of the rough eye phenotype resulting from overexpression of the Notch antagonist hairless in Drosophila. Schreiber, S.L., Preiss, A., Nagel, A.C., Wech, I., Maier, D. Genesis (2002) [Pubmed]
  47. Ectopic expression of lunatic Fringe leads to downregulation of Serrate-1 in the developing chick neural tube; analysis using in ovo electroporation transfection technique. Sakamoto, K., Nakamura, H., Takagi, M., Takeda, S., Katsube, K. FEBS Lett. (1998) [Pubmed]
  48. Molecular analysis of a cellular decision during embryonic development of Drosophila melanogaster: epidermogenesis or neurogenesis. Campos-Ortega, J.A., Knust, E. Eur. J. Biochem. (1990) [Pubmed]
 
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