• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of geneticsGeneticsCurrent IssueInformation for AuthorsEditorial BoardSubscribeSubmit a Manuscript
Genetics. Jun 2001; 158(2): 667–679.
PMCID: PMC1461664

A systematic screen for dominant second-site modifiers of Merlin/NF2 phenotypes reveals an interaction with blistered/DSRF and scribbler.

Abstract

Merlin, the Drosophila homologue of the human tumor suppressor gene Neurofibromatosis 2 (NF2), is required for the regulation of cell proliferation and differentiation. To better understand the cellular functions of the NF2 gene product, Merlin, recent work has concentrated on identifying proteins with which it interacts either physically or functionally. In this article, we describe genetic screens designed to isolate second-site modifiers of Merlin phenotypes from which we have identified five multiallelic complementation groups that modify both loss-of-function and dominant-negative Merlin phenotypes. Three of these groups, Group IIa/scribbler (also known as brakeless), Group IIc/blistered, and Group IId/net, are known genes, while two appear to be novel. In addition, two genes, Group IIa/scribbler and Group IIc/blistered, alter Merlin subcellular localization in epithelial and neuronal tissues, suggesting that they regulate Merlin trafficking or function. Furthermore, we show that mutations in scribbler and blistered display second-site noncomplementation with one another. These results suggest that Merlin, blistered, and scribbler function together in a common pathway to regulate Drosophila wing epithelial development.

Full Text

The Full Text of this article is available as a PDF (559K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Algrain M, Turunen O, Vaheri A, Louvard D, Arpin M. Ezrin contains cytoskeleton and membrane binding domains accounting for its proposed role as a membrane-cytoskeletal linker. J Cell Biol. 1993 Jan;120(1):129–139. [PMC free article] [PubMed]
  • Biehs B, Sturtevant MA, Bier E. Boundaries in the Drosophila wing imaginal disc organize vein-specific genetic programs. Development. 1998 Nov;125(21):4245–4257. [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]
  • Bruder CE, Ichimura K, Tingby O, Hirakawa K, Komatsuzaki A, Tamura A, Yuasa Y, Collins VP, Dumanski JP. A group of schwannomas with interstitial deletions on 22q located outside the NF2 locus shows no detectable mutations in the NF2 gene. Hum Genet. 1999 May;104(5):418–424. [PubMed]
  • Bruder CE, Ichimura K, Blennow E, Ikeuchi T, Yamaguchi T, Yuasa Y, Collins VP, Dumanski JP. Severe phenotype of neurofibromatosis type 2 in a patient with a 7.4-MB constitutional deletion on chromosome 22: possible localization of a neurofibromatosis type 2 modifier gene? Genes Chromosomes Cancer. 1999 Jun;25(2):184–190. [PubMed]
  • Chishti AH, Kim AC, Marfatia SM, Lutchman M, Hanspal M, Jindal H, Liu SC, Low PS, Rouleau GA, Mohandas N, et al. The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane. Trends Biochem Sci. 1998 Aug;23(8):281–282. [PubMed]
  • Fehon RG, Oren T, LaJeunesse DR, Melby TE, McCartney BM. Isolation of mutations in the Drosophila homologues of the human Neurofibromatosis 2 and yeast CDC42 genes using a simple and efficient reverse-genetic method. Genetics. 1997 May;146(1):245–252. [PMC free article] [PubMed]
  • Fristrom D, Gotwals P, Eaton S, Kornberg TB, Sturtevant M, Bier E, Fristrom JW. Blistered: a gene required for vein/intervein formation in wings of Drosophila. Development. 1994 Sep;120(9):2661–2671. [PubMed]
  • Grönholm M, Sainio M, Zhao F, Heiska L, Vaheri A, Carpén O. Homotypic and heterotypic interaction of the neurofibromatosis 2 tumor suppressor protein merlin and the ERM protein ezrin. J Cell Sci. 1999 Mar;112(Pt 6):895–904. [PubMed]
  • Guillemin K, Groppe J, Ducker K, Treisman R, Hafen E, Affolter M, Krasnow MA. The pruned gene encodes the Drosophila serum response factor and regulates cytoplasmic outgrowth during terminal branching of the tracheal system. Development. 1996 May;122(5):1353–1362. [PubMed]
  • Halsell SR, Kiehart DP. Second-site noncomplementation identifies genomic regions required for Drosophila nonmuscle myosin function during morphogenesis. Genetics. 1998 Apr;148(4):1845–1863. [PMC free article] [PubMed]
  • Heiska L, Alfthan K, Grönholm M, Vilja P, Vaheri A, Carpén O. Association of ezrin with intercellular adhesion molecule-1 and -2 (ICAM-1 and ICAM-2). Regulation by phosphatidylinositol 4, 5-bisphosphate. J Biol Chem. 1998 Aug 21;273(34):21893–21900. [PubMed]
  • Helander TS, Carpén O, Turunen O, Kovanen PE, Vaheri A, Timonen T. ICAM-2 redistributed by ezrin as a target for killer cells. Nature. 1996 Jul 18;382(6588):265–268. [PubMed]
  • Herrlich P, Morrison H, Sleeman J, Orian-Rousseau V, König H, Weg-Remers S, Ponta H. CD44 acts both as a growth- and invasiveness-promoting molecule and as a tumor-suppressing cofactor. Ann N Y Acad Sci. 2000 Jun;910:106–120. [PubMed]
  • LaJeunesse DR, McCartney BM, Fehon RG. Structural analysis of Drosophila merlin reveals functional domains important for growth control and subcellular localization. J Cell Biol. 1998 Jun 29;141(7):1589–1599. [PMC free article] [PubMed]
  • Littleton JT, Bellen HJ. Genetic and phenotypic analysis of thirteen essential genes in cytological interval 22F1-2; 23B1-2 reveals novel genes required for neural development in Drosophila. Genetics. 1994 Sep;138(1):111–123. [PMC free article] [PubMed]
  • Martuza RL, Eldridge R. Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med. 1988 Mar 17;318(11):684–688. [PubMed]
  • Matsui T, Yonemura S, Tsukita S, Tsukita S. Activation of ERM proteins in vivo by Rho involves phosphatidyl-inositol 4-phosphate 5-kinase and not ROCK kinases. Curr Biol. 1999 Nov 4;9(21):1259–1262. [PubMed]
  • McCartney BM, Fehon RG. Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor, merlin. J Cell Biol. 1996 May;133(4):843–852. [PMC free article] [PubMed]
  • Scoles DR, Huynh DP, Morcos PA, Coulsell ER, Robinson NG, Tamanoi F, Pulst SM. Neurofibromatosis 2 tumour suppressor schwannomin interacts with betaII-spectrin. Nat Genet. 1998 Apr;18(4):354–359. [PubMed]
  • McCartney BM, Kulikauskas RM, LaJeunesse DR, Fehon RG. The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation. Development. 2000 Mar;127(6):1315–1324. [PubMed]
  • Senti K, Keleman K, Eisenhaber F, Dickson BJ. brakeless is required for lamina targeting of R1-R6 axons in the Drosophila visual system. Development. 2000 Jun;127(11):2291–2301. [PubMed]
  • McClatchey AI, Saotome I, Mercer K, Crowley D, Gusella JF, Bronson RT, Jacks T. Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev. 1998 Apr 15;12(8):1121–1133. [PMC free article] [PubMed]
  • Montagne J, Groppe J, Guillemin K, Krasnow MA, Gehring WJ, Affolter M. The Drosophila Serum Response Factor gene is required for the formation of intervein tissue of the wing and is allelic to blistered. Development. 1996 Sep;122(9):2589–2597. [PubMed]
  • Shearn A. The ash-1, ash-2 and trithorax genes of Drosophila melanogaster are functionally related. Genetics. 1989 Mar;121(3):517–525. [PMC free article] [PubMed]
  • Simon MA, Bowtell DD, Dodson GS, Laverty TR, Rubin GM. Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase. Cell. 1991 Nov 15;67(4):701–716. [PubMed]
  • Murthy A, Gonzalez-Agosti C, Cordero E, Pinney D, Candia C, Solomon F, Gusella J, Ramesh V. NHE-RF, a regulatory cofactor for Na(+)-H+ exchange, is a common interactor for merlin and ERM (MERM) proteins. J Biol Chem. 1998 Jan 16;273(3):1273–1276. [PubMed]
  • Sturtevant MA, Bier E. Analysis of the genetic hierarchy guiding wing vein development in Drosophila. Development. 1995 Mar;121(3):785–801. [PubMed]
  • Rao Y, Pang P, Ruan W, Gunning D, Zipursky SL. brakeless is required for photoreceptor growth-cone targeting in Drosophila. Proc Natl Acad Sci U S A. 2000 May 23;97(11):5966–5971. [PMC free article] [PubMed]
  • Tripoulas N, LaJeunesse D, Gildea J, Shearn A. The Drosophila ash1 gene product, which is localized at specific sites on polytene chromosomes, contains a SET domain and a PHD finger. Genetics. 1996 Jun;143(2):913–928. [PMC free article] [PubMed]
  • Rebay I, Chen F, Hsiao F, Kolodziej PA, Kuang BH, Laverty T, Suh C, Voas M, Williams A, Rubin GM. A genetic screen for novel components of the Ras/Mitogen-activated protein kinase signaling pathway that interact with the yan gene of Drosophila identifies split ends, a new RNA recognition motif-containing protein. Genetics. 2000 Feb;154(2):695–712. [PMC free article] [PubMed]
  • Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K, et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993 Mar 12;72(5):791–800. [PubMed]
  • Reczek D, Berryman M, Bretscher A. Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. J Cell Biol. 1997 Oct 6;139(1):169–179. [PMC free article] [PubMed]
  • Tsukita S, Oishi K, Sato N, Sagara J, Kawai A, Tsukita S. ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J Cell Biol. 1994 Jul;126(2):391–401. [PMC free article] [PubMed]
  • Roch F, Baonza A, Martín-Blanco E, García-Bellido A. Genetic interactions and cell behaviour in blistered mutants during proliferation and differentiation of the Drosophila wing. Development. 1998 May;125(10):1823–1832. [PubMed]
  • Xu HM, Gutmann DH. Merlin differentially associates with the microtubule and actin cytoskeleton. J Neurosci Res. 1998 Feb 1;51(3):403–415. [PubMed]
  • Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature. 1993 Jun 10;363(6429):515–521. [PubMed]

Articles from Genetics are provided here courtesy of Genetics Society of America

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...