Skip to main content
Log in

The first deltex null mutant indicates tissue-specific deltex-dependent Notch signaling in Drosophila

  • Original Paper
  • Published:
Molecular Genetics and Genomics Aims and scope Submit manuscript

Abstract

Notch (N) is a single-pass transmembrane receptor. The N signaling pathway is an evolutionarily conserved mechanism that controls various cell-specification processes. Drosophila Deltex (Dx), a RING-domain E3 ubiquitin ligase, binds to the N intracellular domain, promotes N’s endocytic trafficking to late endosomes, and was proposed to activate Suppressor of Hairless [Su(H)]-independent N signaling. However, it has been difficult to evaluate the importance of dx, because no null mutant of a dx family gene has been available in any organism. Here, we report the first null mutant allele of Drosophila dx. We found that dx was involved only in the subsets of N signaling, but was not essential for it in any developmental context. A strong genetic interaction between dx and Su(H) suggested that dx might function in Su(H)-dependent N signaling. Our epistatic analyses suggested that dx functions downstream of the ligands and upstream of activated Su(H). We also uncovered a novel dx activity that suppressed N signaling downstream of N.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Amin A (2004) Genetic cross-talk during head development in Drosophila. J Biomed Biotechnol 2004:16–23

    Article  PubMed  Google Scholar 

  • Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776

    Article  PubMed  CAS  Google Scholar 

  • Bailey AM, Posakony JW (1995) Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. Genes Dev 9:2609–2622

    Article  PubMed  CAS  Google Scholar 

  • Barolo S, Stone T, Bang AG, Posakony JW (2002) Default repression and notch signaling: hairless acts as an adaptor to recruit the corepressors Groucho and dCtBP to suppressor of hairless. Genes Dev 16:1964–1976

    Article  PubMed  CAS  Google Scholar 

  • Bishop SA, Klein T, Arias AM, Couso JP (1999) Composite signalling from serrate and delta establishes leg segments in Drosophila through Notch. Development 126:2993–3003

    PubMed  CAS  Google Scholar 

  • Brennan K, Tateson R, Lewis K, Arias AM (1997) A functional analysis of Notch mutations in Drosophila. Genetics 147:177–188

    PubMed  CAS  Google Scholar 

  • Busseau I, Diederich RJ, Xu T, Artavanis-Tsakonas S (1994) A member of the Notch group of interacting loci, deltex encodes a cytoplasmic basic protein. Genetics 136:585–596

    PubMed  CAS  Google Scholar 

  • Certel K, Hudson A, Carroll SB, Johnson WA (2000) Restricted patterning of vestigial expression in Drosophila wing imaginal discs requires synergistic activation by both Mad and the drifter POU domain transcription factor. Development 127:3173–3183

    PubMed  CAS  Google Scholar 

  • Couso JP, Knust E, Martinez Arias A (1995) Serrate and wingless cooperate to induce vestigial gene expression and wing formation in Drosophila. Curr Biol 5:1437–1448

    Article  PubMed  CAS  Google Scholar 

  • Dan L Lindsley GGZ (1992) The genome of Drosophila melanogaster. Academic, San Diego

    Google Scholar 

  • de Celis JF, Garcia-Bellido A, Bray SJ (1996) Activation and function of Notch at the dorsal-ventral boundary of the wing imaginal disc. Development 122:359–369

    PubMed  Google Scholar 

  • De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398:518–522

    Article  PubMed  CAS  Google Scholar 

  • Diederich RJ, Matsuno K, Hing H, Artavanis-Tsakonas S (1994) Cytosolic interaction between deltex and Notch ankyrin repeats implicates deltex in the Notch signaling pathway. Development 120:473–481

    PubMed  CAS  Google Scholar 

  • Doherty D, Feger G, Younger-Shepherd S, Jan LY, Jan YN (1996) Delta is a ventral to dorsal signal complementary to Serrate, another Notch ligand, in Drosophila wing formation. Genes Dev 10:421–434

    Article  PubMed  CAS  Google Scholar 

  • Endo Y, Osumi N, Wakamatsu Y (2003) Deltex/Dtx mediates NOTCH signaling in regulation of Bmp4 expression in cranial neural crest formation during avian development. Dev Growth Differ 45:241–248

    Article  PubMed  CAS  Google Scholar 

  • Fanto M, Mlodzik M (1999) Asymmetric Notch activation specifies photoreceptors R3 and R4 and planar polarity in the Drosophila eye. Nature 397:523–526

    Article  PubMed  CAS  Google Scholar 

  • Fehon RG, Johansen K, Rebay I, Artavanis-Tsakonas S (1991) Complex cellular and subcellular regulation of notch expression during embryonic and imaginal development of Drosophila: implications for notch function. J Cell Biol 113:657–669

    Article  PubMed  CAS  Google Scholar 

  • Fehon RG, Kooh PJ, Rebay I, Regan CL, Xu T, Muskavitch MA, Artavanis-Tsakonas S (1990) Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell 61:523–534

    Article  PubMed  CAS  Google Scholar 

  • Fleming RJ, Gu Y, Hukriede NA (1997) Serrate-mediated activation of Notch is specifically blocked by the product of the gene fringe in the dorsal compartment of the Drosophila wing imaginal disc. Development 124:2973–2981

    PubMed  CAS  Google Scholar 

  • Fortini ME, Artavanis-Tsakonas S (1994) The suppressor of hairless protein participates in notch receptor signaling. Cell 79:273–282

    Article  PubMed  CAS  Google Scholar 

  • Furriols M, Bray S (2000) Dissecting the mechanisms of suppressor of hairless function. Dev Biol 227:520–532

    Article  PubMed  CAS  Google Scholar 

  • Gorman MJ, Girton JR (1992) A genetic analysis of deltex and its interaction with the Notch locus in Drosophila melanogaster. Genetics 131:99–112

    PubMed  CAS  Google Scholar 

  • Grimwade BG, Muskavitch MA, Welshons WJ, Yedvobnick B, Artavanis-Tsakonas S (1985) The molecular genetics of the Notch locus in Drosophila melanogaster. Dev Biol 107:503–519

    Article  PubMed  CAS  Google Scholar 

  • Gubb D (1993) Genes controlling cellular polarity in Drosophila. Development Suppl:269–277

    Google Scholar 

  • Hansson EM, Lendahl U, Chapman G (2004) Notch signaling in development and disease. Semin Cancer Biol 14:320–328

    Article  PubMed  CAS  Google Scholar 

  • Heitzler P, Simpson P (1991) The choice of cell fate in the epidermis of Drosophila. Cell 64:1083–1092

    Article  PubMed  CAS  Google Scholar 

  • Heitzler P, Simpson P (1993) Altered epidermal growth factor-like sequences provide evidence for a role of Notch as a receptor in cell fate decisions. Development 117:1113–1123

    PubMed  CAS  Google Scholar 

  • Hori K, Fostier M, Ito M, Fuwa TJ, Go MJ, Okano H, Baron M, Matsuno K (2004) Drosophila deltex mediates suppressor of Hairless-independent and late-endosomal activation of Notch signaling. Development 131:5527–5537

    Article  PubMed  CAS  Google Scholar 

  • Horowitz H, Berg CA (1995) Aberrant splicing and transcription termination caused by P element insertion into the intron of a Drosophila gene. Genetics 139:327–335

    PubMed  CAS  Google Scholar 

  • Hu QD, Ang BT, Karsak M, Hu WP, Cui XY, Duka T, Takeda Y, Chia W, Sankar N, Ng YK, Ling EA, Maciag T, Small D, Trifonova R, Kopan R, Okano H, Nakafuku M, Chiba S, Hirai H, Aster JC, Schachner M, Pallen CJ, Watanabe K, Xiao ZC (2003) F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation. Cell 115:163–175

    Article  PubMed  CAS  Google Scholar 

  • Jacobsen TL, Brennan K, Arias AM, Muskavitch MA (1998) Cis-interactions between Delta and Notch modulate neurogenic signalling in Drosophila. Development 125:4531–4540

    PubMed  CAS  Google Scholar 

  • Joazeiro CA, Weissman AM (2000) RING finger proteins: mediators of ubiquitin ligase activity. Cell 102:549–552

    Article  PubMed  CAS  Google Scholar 

  • Johnson RL, Grenier JK, Scott MP (1995) Patched overexpression alters wing disc size and pattern: transcriptional and post-transcriptional effects on hedgehog targets. Development 121:4161–4170

    PubMed  CAS  Google Scholar 

  • Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z, Downes M, Kintner CR, Evans RM, Kadesch T (1998) A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev 12:2269–2277

    Article  PubMed  CAS  Google Scholar 

  • Kidd S, Lockett TJ, Young MW (1983) The Notch locus of Drosophila melanogaster. Cell 34:421–433

    Article  PubMed  CAS  Google Scholar 

  • Kim J, Sebring A, Esch JJ, Kraus ME, Vorwerk K, Magee J, Carroll SB (1996) Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene. Nature 382:133–138

    Article  PubMed  CAS  Google Scholar 

  • Kishi N, Tang Z, Maeda Y, Hirai A, Mo R, Ito M, Suzuki S, Nakao K, Kinoshita T, Kadesch T, Hui C, Artavanis-Tsakonas S, Okano H, Matsuno K (2001) Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis. Int J Dev Neurosci 19:21–35

    Article  PubMed  CAS  Google Scholar 

  • Kitagawa M, Oyama T, Kawashima T, Yedvobnick B, Kumar A, Matsuno K, Harigaya K (2001) A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of notch and a CSL protein to build a transcriptional activator complex on target promoters. Mol Cell Biol 21:4337–4346

    Article  PubMed  CAS  Google Scholar 

  • Klein T, Arias AM (1998) Different spatial and temporal interactions between Notch, wingless, and vestigial specify proximal and distal pattern elements of the wing in Drosophila. Dev Biol 194:196–212

    Article  PubMed  CAS  Google Scholar 

  • Lai EC (2004) Notch signaling: control of cell communication and cell fate. Development 131:965–973

    Article  PubMed  CAS  Google Scholar 

  • Le Borgne R, Bardin A, Schweisguth F (2005) The roles of receptor and ligand endocytosis in regulating Notch signaling. Development 132:1751–1762

    Article  PubMed  CAS  Google Scholar 

  • Lecourtois M, Schweisguth F (1995) 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 9:2598–2608

    Article  PubMed  CAS  Google Scholar 

  • Lieber T, Kidd S, Young MW (2002) kuzbanian-mediated cleavage of Drosophila Notch. Genes Dev 16:209–221

    Article  PubMed  CAS  Google Scholar 

  • Ligoxygakis P, Yu SY, Delidakis C, Baker NE (1998) A subset of notch functions during Drosophila eye development require Su(H) and the E(spl) gene complex. Development 125:2893–2900

    PubMed  CAS  Google Scholar 

  • Liu WH, Lai MZ (2005) Deltex regulates T-cell activation by targeted degradation of active MEKK1. Mol Cell Biol 25:1367–1378

    Article  PubMed  CAS  Google Scholar 

  • Llimargas M (1999) The Notch pathway helps to pattern the tips of the Drosophila tracheal branches by selecting cell fates. Development 126:2355–2364

    PubMed  CAS  Google Scholar 

  • Matsuno K, Diederich RJ, Go MJ, Blaumueller CM, Artavanis-Tsakonas S (1995) Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats. Development 121:2633–2644

    PubMed  CAS  Google Scholar 

  • Matsuno K, Eastman D, Mitsiades T, Quinn AM, Carcanciu ML, Ordentlich P, Kadesch T, Artavanis-Tsakonas S (1998) Human deltex is a conserved regulator of Notch signalling. Nat Genet 19:74–78

    Article  PubMed  CAS  Google Scholar 

  • Matsuno K, Ito M, Hori K, Miyashita F, Suzuki S, Kishi N, Artavanis-Tsakonas S, Okano H (2002) Involvement of a proline-rich motif and RING-H2 finger of Deltex in the regulation of Notch signaling. Development 129:1049–1059

    PubMed  CAS  Google Scholar 

  • Micchelli CA, Blair SS (1999) Dorsoventral lineage restriction in wing imaginal discs requires Notch. Nature 401:473–476

    Article  PubMed  CAS  Google Scholar 

  • Morel V, Schweisguth F (2000) Repression by suppressor of hairless and activation by Notch are required to define a single row of single-minded expressing cells in the Drosophila embryo. Genes Dev 14:377–388

    PubMed  CAS  Google Scholar 

  • Mullis KB, Faloona FA (1987) Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol 155:335–350

    Article  PubMed  CAS  Google Scholar 

  • Mumm JS, Kopan R (2000) Notch signaling: from the outside in. Dev Biol 228:151–165

    Article  PubMed  CAS  Google Scholar 

  • Neumann CJ, Cohen SM (1996) A hierarchy of cross-regulation involving Notch, wingless, vestigial and cut organizes the dorsal/ventral axis of the Drosophila wing. Development 122:3477–3485

    PubMed  CAS  Google Scholar 

  • Ordentlich P, Lin A, Shen CP, Blaumueller C, Matsuno K, Artavanis-Tsakonas S, Kadesch T (1998) Notch inhibition of E47 supports the existence of a novel signaling pathway. Mol Cell Biol 18:2230–2239

    PubMed  CAS  Google Scholar 

  • Pampeno CL, Meruelo D (1996) A novel cDNA transcript expressed in fractionated X-irradiation-induced murine thymomas. Cell Growth Differ 7:1113–1123

    PubMed  CAS  Google Scholar 

  • Pan D, Rubin GM (1997) Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 90:271–280

    Article  PubMed  CAS  Google Scholar 

  • Panin VM, Papayannopoulos V, Wilson R, Irvine KD (1997) Fringe modulates Notch-ligand interactions. Nature 387:908–912

    Article  PubMed  CAS  Google Scholar 

  • Parks AL, Muskavitch MA (1993) Delta function is required for bristle organ determination and morphogenesis in Drosophila. Dev Biol 157:484–496

    Article  PubMed  CAS  Google Scholar 

  • Qiu L, Joazeiro C, Fang N, Wang HY, Elly C, Altman Y, Fang D, Hunter T, Liu YC (2000) Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase. J Biol Chem 275:35734–35737

    Article  PubMed  CAS  Google Scholar 

  • Ramain P, Khechumian K, Seugnet L, Arbogast N, Ackermann C, Heitzler P (2001) Novel Notch alleles reveal a Deltex-dependent pathway repressing neural fate. Curr Biol 11:1729–1738

    Article  PubMed  CAS  Google Scholar 

  • Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S (1991) Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell 67:687–699

    Article  PubMed  CAS  Google Scholar 

  • Robertson HM, Preston CR, Phillis RW, Johnson-Schlitz DM, Benz WK, Engels WR (1988) A stable genomic source of P element transposase in Drosophila melanogaster. Genetics 118:461–470

    PubMed  CAS  Google Scholar 

  • Rooke J, Pan D, Xu T, Rubin GM (1996) KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis. Science 273:1227–1231

    Article  PubMed  CAS  Google Scholar 

  • Rorth P (1996) A modular misexpression screen in Drosophila detecting tissue-specific phenotypes. Proc Natl Acad Sci USA 93:12418–12422

    Article  PubMed  CAS  Google Scholar 

  • Sakata T, Sakaguchi H, Tsuda L, Higashitani A, Aigaki T, Matsuno K, Hayashi S (2004) Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation. Curr Biol 14:2228–2236

    Article  PubMed  CAS  Google Scholar 

  • Sestan N, Artavanis-Tsakonas S, Rakic P (1999) Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 286:741–746

    Article  PubMed  CAS  Google Scholar 

  • Shellenbarger DL, Mohler JD (1975) Temperature-sensitive mutations of the notch locus in Drosophila melanogaster. Genetics 81:143–162

    PubMed  CAS  Google Scholar 

  • Shepard SB, Broverman SA, Muskavitch MA (1989) A tripartite interaction among alleles of Notch, Delta, and Enhancer of split during imaginal development of Drosophila melanogaster. Genetics 122:429–438

    PubMed  CAS  Google Scholar 

  • Speicher SA, Thomas U, Hinz U, Knust E (1994) The Serrate locus of Drosophila and its role in morphogenesis of the wing imaginal discs: control of cell proliferation. Development 120:535–544

    PubMed  CAS  Google Scholar 

  • Struhl G, Greenwald I (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398:522–525

    Article  PubMed  CAS  Google Scholar 

  • Struhl G, Greenwald I (2001) Presenilin-mediated transmembrane cleavage is required for Notch signal transduction in Drosophila. Proc Natl Acad Sci USA 98:229–234

    Article  PubMed  CAS  Google Scholar 

  • Takeyama K, Aguiar RC, Gu L, He C, Freeman GJ, Kutok JL, Aster JC, Shipp MA (2003) The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity. J Biol Chem 278:21930–21937

    Article  PubMed  CAS  Google Scholar 

  • Theisen H, Purcell J, Bennett M, Kansagara D, Syed A, Marsh JL (1994) dishevelled is required during wingless signaling to establish both cell polarity and cell identity. Development 120:347–360

    PubMed  CAS  Google Scholar 

  • Tramboo NA, Iqbal K, Dar MA, Malik RA, Naikoo BA, Andrabi MA (2002) Unusual dysmorphic features in five patients with Noonan’s syndrome: a brief review. J Paediatr Child Health 38:521–525

    Article  PubMed  CAS  Google Scholar 

  • van den Heuvel M, Nusse R, Johnston P, Lawrence PA (1989) Distribution of the wingless gene product in Drosophila embryos: a protein involved in cell-cell communication. Cell 59:739–749

    Article  PubMed  Google Scholar 

  • Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S (1985) Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 43:567–581

    Article  PubMed  CAS  Google Scholar 

  • Wilkin MB, Carbery AM, Fostier M, Aslam H, Mazaleyrat SL, Higgs J, Myat A, Evans DA, Cornell M, Baron M (2004) Regulation of notch endosomal sorting and signaling by Drosophila Nedd4 family proteins. Curr Biol 14:2237–2244

    Article  PubMed  CAS  Google Scholar 

  • Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD (2000) MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet 26:484–489

    Article  PubMed  CAS  Google Scholar 

  • Xu T, Artavanis-Tsakonas S (1990a) Deltex, a locus interacting with the neurogenic genes, Notch, Delta and mastermind in Drosophila melanogaster. Genetics 126:665–677

    CAS  Google Scholar 

  • Xu T, Rebay I, Fleming RJ, Scottgale TN, Artavanis-Tsakonas S (1990b) The Notch locus and the genetic circuitry involved in early Drosophila neurogenesis. Genes Dev 4:464–475

    Article  CAS  Google Scholar 

  • Xu T, Rubin GM (1993) Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117:1223–1237

    PubMed  CAS  Google Scholar 

  • Zecchini V, Brennan K, Martinez-Arias A (1999) An activity of Notch regulates JNK signalling and affects dorsal closure in Drosophila. Curr Biol 9:460–469

    Article  PubMed  CAS  Google Scholar 

  • Zeng C, Younger-Shepherd S, Jan LY, Jan YN (1998) Delta and Serrate are redundant Notch ligands required for asymmetric cell divisions within the Drosophila sensory organ lineage. Genes Dev 12:1086–1091

    Article  PubMed  CAS  Google Scholar 

  • Zhang YQ, Matthies HJ, Mancuso J, Andrews HK, Woodruff E, 3rd, Friedman D, Broadie K (2004) The Drosophila fragile X-related gene regulates axoneme differentiation during spermatogenesis. Dev Biol 270:290–307

    Article  PubMed  CAS  Google Scholar 

  • Zheng L, Zhang J, Carthew RW (1995) frizzled regulates mirror-symmetric pattern formation in the Drosophila eye. Development 121:3045–3055

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Developmental Studies Hybridoma Bank, University of Iowa and the Bloomington Stock Center. We thank all laboratory members for discussions and comments on this work. This work was supported by a grant-in-aid from the Japanese Ministry of Education, Culture, Sports and Science, funded by PRESTO.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kenji Matsuno.

Additional information

Communicated by G. Reuter

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fuwa, T.J., Hori, K., Sasamura, T. et al. The first deltex null mutant indicates tissue-specific deltex-dependent Notch signaling in Drosophila . Mol Genet Genomics 275, 251–263 (2006). https://doi.org/10.1007/s00438-005-0087-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00438-005-0087-3

Keywords

Navigation