Advertisement
JOURNAL ARTICLES
Germ-line tumor formation caused by activation of glp-1, a Caenorhabditis elegans member of the Notch family of receptors
L.W. Berry, B. Westlund, T. Schedl
Development 1997 124: 925-936;

Summary

Caenorhabditis elegans germ-line proliferation is controlled by an inductive interaction between the somatic distal tip cell and the germ line. GLP-1, a member of the Notch family of transmembrane receptors, is required continuously in the germ line to transduce the proliferative signal. In the absence of GLP-1, all proliferative germ cells exit the mitotic cell cycle and enter meiotic prophase. We have characterized an activating mutation in glp-1, oz112gf, that has the opposite phenotype. Homozygous glp-1(oz112gf) hermaphrodites and males have a completely tumorous germ line in which germ cells never leave the mitotic cycle. In glp-1(oz112gf) heterozygotes, germ-line polarity is established correctly, but as adults age, the distal proliferative population expands leading to a late-onset tumorous phenotype. The mutant receptor is constitutively active, promoting proliferation in the absence of ligand. The normal distal-proximal spatial restriction of GLP-1 expression is lost in tumorous and late-onset tumorous animals; ectopically proliferating germ cells contain membrane-associated GLP-1. The correlation between proliferation and expression, both in wild-type where glp-1 signalling is limited by localized ligand and in glp-1(oz112gf) where signalling is ligand-independent, suggests that glp-1 signalling positively regulates GLP-1 expression. In addition to germ-line defects, glp-1(oz112gf) causes inappropriate vulval cell fate specification. A missense mutation in a conserved extracellular residue, Ser642, adjacent to the transmembrane domain, is sufficient to confer the glp-1(oz112gf) mutant phenotypes. Two mammalian Notch family members, TAN-1 and int-3, are proto-oncogenes. Thus, activating mutations in both invertebrate and vertebrate Notch family members can lead to tumor formation.

REFERENCES

    1. Artavanis-Tsakonas S.,
    2. Matsuno K.,
    3. Fortini M. E.
    (1995) Notch signaling. Science 268, 225–232
    OpenUrlAbstract/FREE Full Text
    1. Austin J.,
    2. Kimble J.
    (1987) glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans. Cell 51, 589–599
    OpenUrlCrossRefPubMedWeb of Science
    1. Bishop J.
    (1991) Molecular themes in oncogenesis. Cell 64, 235–248
    OpenUrlCrossRefPubMedWeb of Science
    1. Bowerman B.
    (1995) Determinants of blastomere identity in the early C. elegans embryo.BioEssays 17, 404–414
    OpenUrl
    1. Brenner S.
    (1974) The genetics of Caenorhabditis elegans. Genetics 77, 71–94
    OpenUrlAbstract/FREE Full Text
    1. Christensen S.,
    2. Kodoyianni V.,
    3. Bosenberg M.,
    4. Friedman L.,
    5. Kimble J.
    (1996) lag-1, a gene required for lin-12 and glp-1 signalling in Caenorhabditis elegans, is homologous to human CBF1 and Drosophila Su(H). Development 122, 1373–1383
    OpenUrlAbstract
    1. Crittenden S. L.,
    2. Troemel E. R.,
    3. Evans T. C.,
    4. Kimble J.
    (1994) GLP-1 is localized to the mitotic region of the C. elegans germ line. Development 120, 2901–2911
    OpenUrlAbstract
    1. Ellis R. E.,
    2. Kimble J.
    (1995) The fog-3 gene and regulation of cell fate in the germ line of Caenorhabditis elegans. Genetics 139, 561–577
    OpenUrlAbstract/FREE Full Text
    1. Ellisen L. W.,
    2. Bird J.,
    3. West D. C.,
    4. Soreng A. L.,
    5. Reynolds T. C.,
    6. Smith S. D.,
    7. Sklar J.
    (1991) TAN1, the human homolog of the Drosophila Notch gene, is broken by chromosomally translocations in T lymphoblastic neoplasms. Cell 66, 649–661
    OpenUrlCrossRefPubMedWeb of Science
    1. Evans T. C.,
    2. Crittenden S. L.,
    3. Kodoyianni V.,
    4. Kimble J.
    (1994) Translational control of maternal glp-1 mRNA establishes an asymmetry in the C. elegans embryo. Cell 77, 183–194
    OpenUrlCrossRefPubMedWeb of Science
    1. Fitzgerald K.,
    2. Wilkinson H.,
    3. Greenwald I.
    (1993) glp-1 can substitute for lin-12 in specifying cell fate decisions in Caenorhabditis elegans. Development 119, 1019–1027
    OpenUrlAbstract
    1. Fitzgerald K.,
    2. Greenwald I.
    (1995) Interchangeability of Caenorhabditis elegans DSL proteins and intrinsic signalling activity of their extracellular domains in vivo. Development 121, 4275–4282
    OpenUrlAbstract
    1. Francis R.,
    2. Barton M. K.,
    3. Kimble J.,
    4. Schedl T.
    (1995) gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans. Genetics 139, 579–606
    OpenUrlAbstract/FREE Full Text
    1. Francis R.,
    2. Maine E.,
    3. Schedl T.
    (1995) Analysis of the multiple roles of gld-1 in germline development: interactions with the sex determination cascade and the glp-1 signaling pathway. Genetics 139, 607–630
    OpenUrlAbstract/FREE Full Text
    1. Greenwald I. S.,
    2. Sternberg P. W.,
    3. Horvitz H.R.
    (1983) The lin-12 locus specifies cell fates in Caenorhabditis elegans. Cell 34, 435–444
    OpenUrlCrossRefPubMedWeb of Science
    1. Greenwald I.,
    2. Seydoux G.
    (1990) Analysis of gain-of-function mutations of the lin-12 gene of Caenorhabditis elegans. Nature 346, 197–199
    OpenUrlCrossRefPubMed
    1. Greenwald I.,
    2. Rubin G.
    (1992) Making a difference: The role of cell-cell interactions in establishing separate identities for equivalent cells. Cell 68, 271–281
    OpenUrlCrossRefPubMedWeb of Science
    1. Greenwald I.
    (1994) Structure/function studies of LIN-12/Notch proteins. Current Opinion Genet. Dev 4, 556–562
    OpenUrlCrossRefPubMed
    1. Henderson S. T.,
    2. Gao D.,
    3. Lambie E. J.,
    4. Kimble J.
    (1994) lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans. Development 120, 2913–2924
    OpenUrlAbstract
    1. Hodgkin J.,
    2. Barnes T.
    (1991) More is not better: brood size and population growth in a self-fertilizing nematode. Proc. R. Soc. Lond. B 246, 19–24
    OpenUrlPubMed
    1. Jhappan C.,
    2. Gallahan D.,
    3. Stahle C.,
    4. Chu E.,
    5. Smith G. H.,
    6. Merlino G.,
    7. Callahan R.
    (1992) Expression of an activated Notch -related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev 6, 345–355
    OpenUrlAbstract/FREE Full Text
    1. Jones A.,
    2. Schedl T.
    (1995) Mutations in gld-1, a female germ cell-specific tumor suppressor gene in Caenorhabditis elegans, affect a conserved domain also found in Src-associated protein Sam68. Genes Dev 9, 1491–1504
    OpenUrlAbstract/FREE Full Text
    1. Kimble J.,
    2. Hirsh D.
    (1979) Postembryonic cell lineages of the hermaphrodite and male gonads in Caenorhabditis elegans. Dev. Biol 70, 396–417
    OpenUrlCrossRefPubMedWeb of Science
    1. Kimble J.
    (1981) Alterations in cell lineage following laser ablation of cells in the somatic gonad of Caenorhabditis elegans. Dev. Biol 87, 286–300
    OpenUrlCrossRefPubMedWeb of Science
    1. Kimble J. E.,
    2. White J. G.
    (1981) On the control of germ cell development in Caenorhabditis elegans. Dev. Biol 81, 208–219
    OpenUrlCrossRefPubMedWeb of Science
    1. Kodoyianni V.,
    2. Maine E.,
    3. Kimble J.
    (1992) Molecular basis of loss-of-function mutations in the glp-1 gene of Caenorhabditis elegans. Mol. Biol. Cell 3, 1199–1213
    OpenUrlAbstract/FREE Full Text
    1. Lambie E. J.,
    2. Kimble J.
    (1991) Genetic control of cell interactions in nematode development. Annu. Rev. Genet 25, 411–436
    OpenUrlCrossRefPubMed
    1. Lambie E. J.,
    2. Kimble J.
    (1991) Two homologous regulatory genes, lin-12 and glp-1, have overlapping functions. Development 112, 231–240
    OpenUrlAbstract
    1. Lissemore J.,
    2. Currie P.,
    3. Turk C.,
    4. Maine E.
    (1993) Intragenic dominantsuppressors of glp-1, a gene essential for cell-signaling in Caenorhabditis elegans, support a role for cdc10/SWI6/ankyrin motifs in GLP-1 function. Genetics 135, 1023–1034
    OpenUrlAbstract/FREE Full Text
    1. Lyman D.,
    2. Young M.
    (1993) Further evidence for function of the Drosophila Notch protein as a transmembrane receptor. Proc. Natl. Acad. Sci. USA 90, 10395–10399
    OpenUrlAbstract/FREE Full Text
    1. Maine E. M.,
    2. Lissemore J. L.,
    3. Starmer W. T.
    (1995) A phylogenetic analysis of vertebrate and invertebrate Notch -related genes. Molecular Phylogenetics and Evolution 4, 139–155
    OpenUrlCrossRefPubMedWeb of Science
    1. Mango S. E.,
    2. Maine E. M.,
    3. Kimble J.
    (1991) Carboxy-terminal truncation activates glp-1 protein to specify vulval fates in Caenorhabditis elegans. Nature 352, 811–815
    OpenUrlCrossRefPubMed
    1. Mello C. C.,
    2. Kramer J. M.,
    3. Stinchcomb D.,
    4. Ambros V.
    (1991) Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J 10, 3959–3970
    OpenUrlPubMedWeb of Science
    1. Robbins J.,
    2. Blondel B. J.,
    3. Gallahan D.,
    4. Callahan R.
    (1992) Mouse mammary tumor gene int-3: a member of the notch gene family transforms mammary epithelial cells. J. Virol 66, 2594–2599
    OpenUrlAbstract/FREE Full Text
    1. Roehl H.,
    2. Kimble J.
    (1993) Control of cell fate in C. elegans by a glp-1 peptide consisting primarily of ankyrin repeats. Nature 364, 632–635
    OpenUrlCrossRefPubMed
    1. Rosenbluth R. E.,
    2. Cuddeford C.,
    3. Baillie D. L.
    (1983) Mutagenesis in Caenorhabditis elegans. I. A rapid eukaryotic mutagen test system using the reciprocal translocation eT1(III,V). Mutat. Res 110, 39–48
    OpenUrl
    1. Sawyers C.,
    2. Denny C.,
    3. Witte O.
    (1991) Leukemia and the disruption of normal hematopoiesis. Cell 64, 337–350
    OpenUrlCrossRefPubMedWeb of Science
    1. Seydoux G.,
    2. Schedl T.,
    3. Greenwald I.
    (1990) Cell-cell interactions prevent a potential inductive interaction between soma and germ line in Caenorhabditis elegans. Cell 61, 939–951
    OpenUrlCrossRefPubMedWeb of Science
    1. Skakkebaek N.,
    2. Berthelsen J.,
    3. Giwercman A.,
    4. Muller J.
    (1987) Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumors except spermatocytoma. Internat. J. Androl 10, 19–28
    OpenUrlCrossRefPubMedWeb of Science
    1. Sternberg P. W.,
    2. Horvitz H.R.
    (1986) Pattern formation during vulval development in C. elegans. Cell 44, 761–772
    OpenUrlCrossRefPubMedWeb of Science
    1. Sulston J. E.,
    2. Horvitz H. R.
    (1977) Post-embryonic cell lineages of the nematode Caenorhabditis elegans. Dev. Biol 56, 110–156
    OpenUrlCrossRefPubMedWeb of Science
    1. Surti I.,
    2. Hoffner L.,
    3. Chakravarti A.,
    4. Ferrell R.
    (1990) Genetics and Biology of human ovarian teratomas. I. Cytogenetic analysis of mechanism of origin. Am. J. Hum. Genet 47, 635–643
    OpenUrlPubMedWeb of Science
    1. Tax F. E.,
    2. Yeargers J. J.,
    3. Thomas J. H.
    (1994) Sequence of C. elegans lag-2 reveals a cell-signalling domain shared with Delta and Serrate of Drosophila. Nature 368, 150–154
    OpenUrlCrossRefPubMed
    1. Wilkinson H. A.,
    2. Fitzgerald K.,
    3. Greenwald I.
    (1994) Reciprocal changes in expression of the receptor lin-12 and its ligand lag-2 prior to commitment in a C. elegans cell fate decision. Cell 79, 1187–1196
    OpenUrlCrossRefPubMedWeb of Science
    1. Williams B. D.,
    2. Schrank B.,
    3. Huynh C.,
    4. Schownkeen R.,
    5. Waterston R. H.
    (1992) A genetic mapping system in Caenorhabditis elegans based on polymorphic sequence-tagged sites. Genetics 131, 609–624
    OpenUrlAbstract/FREE Full Text
    1. Yochem J.,
    2. Greenwald I.
    (1989) glp-1 and lin-12, genes implicated in distinct cell-cell interactions in C. elegans, encode similar transmembrane proteins. Cell 58, 553–563
    OpenUrlCrossRefPubMedWeb of Science
Back to top

 Download PDF

Email
JOURNAL ARTICLES
Germ-line tumor formation caused by activation of glp-1, a Caenorhabditis elegans member of the Notch family of receptors
L.W. Berry, B. Westlund, T. Schedl
Development 1997 124: 925-936;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Alerts

Article navigation

Other journals from The Company of Biologists

Advertisement

An interview with Swathi Arur

Swathi Arur joined the team at Development as an Academic Editor in 2020. Her lab uses multidisciplinary approaches to understand female germline development and fertility. We met with her over Zoom to hear more about her life, her career and her love for C. elegans.

Jim Wells and Hanna Mikkola join our team of Editors

We are pleased to welcome James (Jim) Wells and Hanna Mikkola to our team of Editors. Jim joins us a new Academic Editor, taking over from Gordan Keller, and Hanna joins our team of Associate Editors. Find out more about their research interests and areas of expertise.

New funding scheme supports sustainable events

As part of our Sustainable Conferencing Initiative, we are pleased to announce funding for organisers that seek to reduce the environmental footprint of their event. The next deadline to apply for a Scientific Meeting grant is 26 March 2021.

Read & Publish participation continues to grow

“I’d heard of Read & Publish deals and knew that many universities, including mine, had signed up to them but I had not previously understood the benefits that these deals bring to authors who work at those universities.”

Professor Sally Lowell (University of Edinburgh) shares her experience of publishing Open Access as part of our growing Read & Publish initiative. We now have over 150 institutions in 15 countries and four library consortia taking part – find out more and view our full list of participating institutions.

Upcoming special issues

Imaging Development, Stem Cells and Regeneration
Submission deadline: 30 March 2021
Publication: mid-2021

The Immune System in Development and Regeneration
Guest editors: Florent Ginhoux and Paul Martin
Submission deadline: 1 September 2021
Publication: Spring 2022

Both special issues welcome Review articles as well as Research articles, and will be widely promoted online and at key global conferences.

Development presents...

Our successful webinar series continues into 2021, with early-career researchers presenting their papers and a chance to virtually network with the developmental biology community afterwards. Here, Michèle Romanos talks about her new preprint, which mixes experimentation in quail embryos and computational modelling to understand how heterogeneity in a tissue influences cell rate.

Save your spot at our next session:

10 March
Time: 9:00 (GMT)
Chaired by: Thomas Lecuit

Join our mailing list to receive news and updates on the series.