• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Dec 15, 1998; 17(24): 7351–7360.
PMCID: PMC1171080

Notchless encodes a novel WD40-repeat-containing protein that modulates Notch signaling activity.

Abstract

Signaling by Notch family receptors is involved in many cell-fate decisions during development. Several modifiers of Notch activity have been identified, suggesting that regulation of Notch signaling is complex. In a genetic screen for modifiers of Notch activity, we identified a gene encoding a novel WD40-repeat protein. The gene is called Notchless, because loss-of-function mutant alleles dominantly suppress the wing notching caused by certain Notch alleles. Reducing Notchless activity increases Notch activity. Overexpression of Notchless in Xenopus or Drosophila appears to have a dominant-negative effect in that it also increases Notch activity. Biochemical studies show that Notchless binds to the cytoplasmic domain of Notch, suggesting that it serves as a direct regulator of Notch signaling activity.

Full Text

The Full Text of this article is available as a PDF (505K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science. 1995 Apr 14;268(5208):225–232. [PubMed]
  • Axelrod JD, Matsuno K, Artavanis-Tsakonas S, Perrimon N. Interaction between Wingless and Notch signaling pathways mediated by dishevelled. Science. 1996 Mar 29;271(5257):1826–1832. [PubMed]
  • Bai C, Sen P, Hofmann K, Ma L, Goebl M, Harper JW, Elledge SJ. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell. 1996 Jul 26;86(2):263–274. [PubMed]
  • Bailey AM, Posakony JW. Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. Genes Dev. 1995 Nov 1;9(21):2609–2622. [PubMed]
  • Bouwmeester T, Kim S, Sasai Y, Lu B, De Robertis EM. Cerberus is a head-inducing secreted factor expressed in the anterior endoderm of Spemann's organizer. Nature. 1996 Aug 15;382(6592):595–601. [PubMed]
  • Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993 Jun;118(2):401–415. [PubMed]
  • Brennan K, Tateson R, Lewis K, Arias AM. A functional analysis of Notch mutations in Drosophila. Genetics. 1997 Sep;147(1):177–188. [PMC free article] [PubMed]
  • Brook WJ, Cohen SM. Antagonistic interactions between wingless and decapentaplegic responsible for dorsal-ventral pattern in the Drosophila Leg. Science. 1996 Sep 6;273(5280):1373–1377. [PubMed]
  • Campos-Ortega JA, Jan YN. Genetic and molecular bases of neurogenesis in Drosophila melanogaster. Annu Rev Neurosci. 1991;14:399–420. [PubMed]
  • Chitnis A, Henrique D, Lewis J, Ish-Horowicz D, Kintner C. Primary neurogenesis in Xenopus embryos regulated by a homologue of the Drosophila neurogenic gene Delta. Nature. 1995 Jun 29;375(6534):761–766. [PubMed]
  • Coffman CR, Skoglund P, Harris WA, Kintner CR. Expression of an extracellular deletion of Xotch diverts cell fate in Xenopus embryos. Cell. 1993 May 21;73(4):659–671. [PubMed]
  • Couso JP, Martinez Arias A. Notch is required for wingless signaling in the epidermis of Drosophila. Cell. 1994 Oct 21;79(2):259–272. [PubMed]
  • Couso JP, Bishop SA, Martinez Arias A. The wingless signalling pathway and the patterning of the wing margin in Drosophila. Development. 1994 Mar;120(3):621–636. [PubMed]
  • Couso JP, Knust E, Martinez Arias A. Serrate and wingless cooperate to induce vestigial gene expression and wing formation in Drosophila. Curr Biol. 1995 Dec 1;5(12):1437–1448. [PubMed]
  • de Celis JF, Garcia-Bellido A. Modifications of the notch function by Abruptex mutations in Drosophila melanogaster. Genetics. 1994 Jan;136(1):183–194. [PMC free article] [PubMed]
  • de Celis JF, Bray S. Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. Development. 1997 Sep;124(17):3241–3251. [PubMed]
  • Diaz-Benjumea FJ, Cohen SM. Serrate signals through Notch to establish a Wingless-dependent organizer at the dorsal/ventral compartment boundary of the Drosophila wing. Development. 1995 Dec;121(12):4215–4225. [PubMed]
  • Diederich RJ, Matsuno K, Hing H, Artavanis-Tsakonas S. Cytosolic interaction between deltex and Notch ankyrin repeats implicates deltex in the Notch signaling pathway. Development. 1994 Mar;120(3):473–481. [PubMed]
  • Fehon RG, Kooh PJ, Rebay I, Regan CL, Xu T, Muskavitch MA, Artavanis-Tsakonas S. Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell. 1990 May 4;61(3):523–534. [PubMed]
  • Fortini ME, Artavanis-Tsakonas S. The suppressor of hairless protein participates in notch receptor signaling. Cell. 1994 Oct 21;79(2):273–282. [PubMed]
  • Fortini ME, Rebay I, Caron LA, Artavanis-Tsakonas S. An activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye. Nature. 1993 Oct 7;365(6446):555–557. [PubMed]
  • Frise E, Knoblich JA, Younger-Shepherd S, Jan LY, Jan YN. The Drosophila Numb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11925–11932. [PMC free article] [PubMed]
  • Gridley T. Notch signaling in vertebrate development and disease. Mol Cell Neurosci. 1997;9(2):103–108. [PubMed]
  • Guo M, Jan LY, Jan YN. Control of daughter cell fates during asymmetric division: interaction of Numb and Notch. Neuron. 1996 Jul;17(1):27–41. [PubMed]
  • Heitzler P, Simpson P. The choice of cell fate in the epidermis of Drosophila. Cell. 1991 Mar 22;64(6):1083–1092. [PubMed]
  • Henrique D, Adam J, Myat A, Chitnis A, Lewis J, Ish-Horowicz D. Expression of a Delta homologue in prospective neurons in the chick. Nature. 1995 Jun 29;375(6534):787–790. [PubMed]
  • Hing HK, Sun X, Artavanis-Tsakonas S. Modulation of wingless signaling by Notch in Drosophila. Mech Dev. 1994 Sep;47(3):261–268. [PubMed]
  • Hubbard EJ, Wu G, Kitajewski J, Greenwald I. sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins. Genes Dev. 1997 Dec 1;11(23):3182–3193. [PMC free article] [PubMed]
  • Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A. Signalling downstream of activated mammalian Notch. Nature. 1995 Sep 28;377(6547):355–358. [PubMed]
  • Jen WC, Wettstein D, Turner D, Chitnis A, Kintner C. The Notch ligand, X-Delta-2, mediates segmentation of the paraxial mesoderm in Xenopus embryos. Development. 1997 Mar;124(6):1169–1178. [PubMed]
  • Kim J, Irvine KD, Carroll SB. Cell recognition, signal induction, and symmetrical gene activation at the dorsal-ventral boundary of the developing Drosophila wing. Cell. 1995 Sep 8;82(5):795–802. [PubMed]
  • Kim J, Sebring A, Esch JJ, Kraus ME, Vorwerk K, Magee J, Carroll SB. Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene. Nature. 1996 Jul 11;382(6587):133–138. [PubMed]
  • Kimble J, Simpson P. The LIN-12/Notch signaling pathway and its regulation. Annu Rev Cell Dev Biol. 1997;13:333–361. [PubMed]
  • Knoblich JA, Jan LY, Jan YN. Asymmetric segregation of Numb and Prospero during cell division. Nature. 1995 Oct 19;377(6550):624–627. [PubMed]
  • Kopan R, Nye JS, Weintraub H. The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. Development. 1994 Sep;120(9):2385–2396. [PubMed]
  • Kopan R, Schroeter EH, Weintraub H, Nye JS. Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1683–1688. [PMC free article] [PubMed]
  • 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 Nov 1;9(21):2598–2608. [PubMed]
  • Lieber T, Kidd S, Alcamo E, Corbin V, Young MW. Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei. Genes Dev. 1993 Oct;7(10):1949–1965. [PubMed]
  • Matsuno K, Diederich RJ, Go MJ, Blaumueller CM, Artavanis-Tsakonas S. Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats. Development. 1995 Aug;121(8):2633–2644. [PubMed]
  • Micchelli CA, Rulifson EJ, Blair SS. The function and regulation of cut expression on the wing margin of Drosophila: Notch, Wingless and a dominant negative role for Delta and Serrate. Development. 1997 Apr;124(8):1485–1495. [PubMed]
  • Neer EJ, Smith TF. G protein heterodimers: new structures propel new questions. Cell. 1996 Jan 26;84(2):175–178. [PubMed]
  • Neer EJ, Schmidt CJ, Nambudripad R, Smith TF. The ancient regulatory-protein family of WD-repeat proteins. Nature. 1994 Sep 22;371(6495):297–300. [PubMed]
  • Neumann CJ, Cohen SM. A hierarchy of cross-regulation involving Notch, wingless, vestigial and cut organizes the dorsal/ventral axis of the Drosophila wing. Development. 1996 Nov;122(11):3477–3485. [PubMed]
  • Pan D, Rubin GM. Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell. 1997 Jul 25;90(2):271–280. [PubMed]
  • Rebay I, Fehon RG, Artavanis-Tsakonas S. Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor. Cell. 1993 Jul 30;74(2):319–329. [PubMed]
  • Rhyu MS, Jan LY, Jan YN. Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells. Cell. 1994 Feb 11;76(3):477–491. [PubMed]
  • Robey E. Notch in vertebrates. Curr Opin Genet Dev. 1997 Aug;7(4):551–557. [PubMed]
  • Rulifson EJ, Blair SS. Notch regulates wingless expression and is not required for reception of the paracrine wingless signal during wing margin neurogenesis in Drosophila. Development. 1995 Sep;121(9):2813–2824. [PubMed]
  • Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature. 1998 May 28;393(6683):382–386. [PubMed]
  • Schweisguth F, Posakony JW. Suppressor of Hairless, the Drosophila homolog of the mouse recombination signal-binding protein gene, controls sensory organ cell fates. Cell. 1992 Jun 26;69(7):1199–1212. [PubMed]
  • Spradling AC, Stern DM, Kiss I, Roote J, Laverty T, Rubin GM. Gene disruptions using P transposable elements: an integral component of the Drosophila genome project. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):10824–10830. [PMC free article] [PubMed]
  • Struhl G, Adachi A. Nuclear access and action of notch in vivo. Cell. 1998 May 15;93(4):649–660. [PubMed]
  • Struhl G, Fitzgerald K, Greenwald I. Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo. Cell. 1993 Jul 30;74(2):331–345. [PubMed]
  • Xu T, Rebay I, Fleming RJ, Scottgale TN, Artavanis-Tsakonas S. The Notch locus and the genetic circuitry involved in early Drosophila neurogenesis. Genes Dev. 1990 Mar;4(3):464–475. [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...