Germ-line tumor formation caused by activation of glp-1, a Caenorhabditis elegans member of the Notch family of receptors

Development ◽  
1997 ◽  
Vol 124 (4) ◽  
pp. 925-936 ◽  
Author(s):  
L.W. Berry ◽  
B. Westlund ◽  
T. Schedl
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Germ Cells ◽  
Transmembrane Domain ◽  
Germ Line ◽  
Late Onset ◽  
Family Members ◽  
Mitotic Cell ◽  
Tumor Formation ◽  
Mutant Phenotypes

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.

The fog-3 gene and regulation of cell fate in the germ line of Caenorhabditis elegans.

Genetics ◽  
1995 ◽  
Vol 139 (2) ◽  
pp. 561-577 ◽  
Author(s):  
R E Ellis ◽  
J Kimble
Keyword(s):  
Caenorhabditis Elegans ◽  
Germ Cell ◽  
Sexual Identity ◽  
Cell Fate ◽  
Germ Cells ◽  
Regulatory Network ◽  
Germ Line ◽  
The Other ◽  
Nematode Caenorhabditis Elegans ◽  
Inhibitory Interactions

Abstract In the nematode Caenorhabditis elegans, germ cells normally adopt one of three fates: mitosis, spermatogenesis or oogenesis. We have identified and characterized the gene fog-3, which is required for germ cells to differentiate as sperm rather than as oocytes. Analysis of double mutants suggests that fog-3 is absolutely required for spermatogenesis and acts at the end of the regulatory hierarchy controlling sex determination for the germ line. By contrast, mutations in fog-3 do not alter the sexual identity of other tissues. We also have characterized the null phenotype of fog-1, another gene required for spermatogenesis; we demonstrate that it too controls the sexual identity of germ cells but not of other tissues. Finally, we have studied the interaction of these two fog genes with gld-1, a gene required for germ cells to undergo oogenesis rather than mitosis. On the basis of these results, we propose that germ-cell fate might be controlled by a set of inhibitory interactions among genes that specify one of three fates: mitosis, spermatogenesis or oogenesis. Such a regulatory network would link the adoption of one germ-cell fate to the suppression of the other two.

scholarly journals A Role for Dynein in the Inhibition of Germ Cell Proliferative Fate

2009 ◽  
Vol 29 (22) ◽  
pp. 6128-6139 ◽  
Author(s):  
Maia Dorsett ◽  
Tim Schedl
Keyword(s):  
Cell Fate ◽  
Germ Cells ◽  
Cellular Proliferation ◽  
Germ Line ◽  
Mitotic Cell ◽  
Nuclear Accumulation ◽  
Dynein Light Chain ◽  
Motor Complex ◽  
Dynein Motor ◽  
Normal Differentiation

ABSTRACT During normal development as well as in diseased states such as cancer, extracellular “niches” often provide cues to proximal cells and activate intracellular pathways. Activation of such signaling pathways in turn instructs cellular proliferation and differentiation. In the Caenorhabditis elegans gonad, GLP-1/Notch signaling instructs germ line stem cells to self-renew through mitotic cell division. As germ cells progressively move out of the niche, they differentiate by entering meiosis and eventually form gametes. In this model system, we uncovered an unexpected role for the dynein motor complex in promoting normal differentiation of proliferating germ cells. We demonstrate that dynein light chain 1 (DLC-1) and its partner, dynein heavy chain 1, inhibit the proliferative cell fate, in part through regulation of METT-10, a conserved putative methyltransferase. We show that DLC-1 physically interacts with METT-10 and promotes both its overall levels and nuclear accumulation. Our results add a new dimension to the processes controlled by the dynein motor complex, demonstrating that dynein can act as an antiproliferative factor.

scholarly journals A Genome-Wide RNAi Screen for Enhancers of a Germline Tumor Phenotype Caused by Elevated GLP-1/Notch Signaling in Caenorhabditis elegans

2020 ◽  
Vol 10 (12) ◽  
pp. 4323-4334
Author(s):  
Diana Dalfó ◽  
Yanhui Ding ◽  
Qifei Liang ◽  
Alex Fong ◽  
Patricia Giselle Cipriani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Caenorhabditis Elegans ◽  
Germ Cells ◽  
Germ Line ◽  
Tumor Formation ◽  
Permissive Temperature ◽  
Germline Development ◽  
Link Type ◽  
Somatic Gonad

Stem cells are tightly controlled in vivo. Both the balance between self-renewal and differentiation and the rate of proliferation are often regulated by multiple factors. The Caenorhabditis elegans hermaphrodite germ line provides a simple and accessible system for studying stem cells in vivo. In this system, GLP-1/Notch activity prevents the differentiation of distal germ cells in response to ligand production from the nearby distal tip cell, thereby supporting a stem cell pool. However, a delay in germline development relative to somatic gonad development can cause a pool of undifferentiated germ cells to persist in response to alternate Notch ligands expressed in the proximal somatic gonad. This pool of undifferentiated germ cells forms a proximal tumor that, in adulthood, blocks the oviduct. This type of “latent niche”-driven proximal tumor is highly penetrant in worms bearing the temperature-sensitive weak gain-of-function mutation glp-1(ar202) at the restrictive temperature. At the permissive temperature, few worms develop tumors. Nevertheless, several interventions elevate the penetrance of proximal tumor formation at the permissive temperature, including reduced insulin signaling or the ablation of distal-most sheath cells. To systematically identify genetic perturbations that enhance proximal tumor formation, we sought genes that, upon RNAi depletion, elevate the percentage of worms bearing proximal germline tumors in glp-1(ar202) at the permissive temperature. We identified 43 genes representing a variety of functional classes, the most enriched of which is “translation”. Some of these genes also influence the distal germ line, and some are conserved genes for which genetic interactions with Notch were not previously known in this system.

scholarly journals glp-3 Is Required for Mitosis and Meiosis in the Caenorhabditis elegans Germ Line

Genetics ◽  
1997 ◽  
Vol 145 (1) ◽  
pp. 111-121 ◽  
Author(s):  
Lisa C Kadyk ◽  
Eric J Lambie ◽  
Judith Kimble
Keyword(s):  
Caenorhabditis Elegans ◽  
Germ Cells ◽  
Germ Line ◽  
Stem Cell Population ◽  
Phenotypic Characterization ◽  
Loss Of Function ◽  
Dapi Staining ◽  
Cell Cycles ◽  
C Elegans ◽  
Mitosis And Meiosis

The germ line is the only tissue in Caenorhabditis elegans in which a stem cell population continues to divide mitotically throughout life; hence the cell cycles of the germ line and the soma are regulated differently. Here we report the genetic and phenotypic characterization of the glp-3 gene. In animals homozygous for each of five recessive loss-of-function alleles, germ cells in both hermaphrodites and males fail to progress through mitosis and meiosis, but somatic cells appear to divide normally. Germ cells in animals grown at 15° appear by DAPI staining to be uniformly arrested at the G2/M transition with <20 germ cells per gonad on average, suggesting a checkpoint-mediated arrest. In contrast, germ cells in mutant animals grown at 25° frequently proliferate slowly during adulthood, eventually forming small germ lines with several hundred germ cells. Nevertheless, cells in these small germ lines never undergo meiosis. Double mutant analysis with mutations in other genes affecting germ cell proliferation supports the idea that glp-3 may encode a gene product that is required for the mitotic and meiotic cell cycles in the C. elegans germ line.

glp-1 can substitute for lin-12 in specifying cell fate decisions in Caenorhabditis elegans

Development ◽  
1993 ◽  
Vol 119 (4) ◽  
pp. 1019-1027 ◽  
Author(s):  
K. Fitzgerald ◽  
H.A. Wilkinson ◽  
I. Greenwald
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Effector Proteins ◽  
Regulatory Sequences ◽  
Animal Kingdom ◽  
Cell Fate Decisions ◽  
Notch Gene ◽  
Epidermal Growth ◽  
Differential Gene ◽  
Mutant Phenotypes

Members of the lin-12/Notch gene family encode receptors for intercellular signals and are found throughout the animal kingdom. In many animals, the presence of at least two lin-12/Notch genes raises the issue of the significance of this duplication and divergence. In Caenorhabditis elegans, two lin-12/Notch genes, lin-12 and glp-1, encode proteins that are 50% identical, with different numbers of epidermal growth factor-like motifs in their extracellular domains. Many of the cell fate decisions mediated by lin-12 and glp-1 are distinct. Here, we express glp-1 protein under the control of lin-12 regulatory sequences in animals lacking endogenous lin-12 activity and find that glp-1 can substitute for lin-12 in mediating cell fate decisions. These results imply that the lin-12 and glp-1 proteins are biochemically interchangeable, sharing common ligand and effector proteins, and that the discrete lin-12 and glp-1 mutant phenotypes result from differential gene expression. In addition, these results suggest that the duplicate lin-12/Notch genes found in vertebrates may also be biochemically interchangeable.

Genetic regulation of entry into meiosis in Caenorhabditis elegans

Development ◽  
1998 ◽  
Vol 125 (10) ◽  
pp. 1803-1813 ◽  
Author(s):  
L.C. Kadyk ◽  
J. Kimble
Keyword(s):  
Signal Transduction ◽  
Caenorhabditis Elegans ◽  
Germ Cells ◽  
Genetic Regulation ◽  
Signal Transduction Pathway ◽  
Mitotic Cell ◽  
Transduction Pathway ◽  
Germline Development ◽  
Large Tumor ◽  
Regulatory Pathways

The Caenorhabditis elegans germline is composed of mitotically dividing cells at the distal end that give rise to meiotic cells more proximally. Specification of the distal region as mitotic relies on induction by the somatic distal tip cell and the glp-1 signal transduction pathway. However, the genetic control over the transition from mitosis to meiosis is not understood. In this paper, we report the identification of a gene, gld-2, that has at least two functions in germline development. First, gld-2 is required for normal progression through meiotic prophase. Second, gld-2 promotes entry into meiosis from the mitotic cell cycle. With respect to this second function, gld-2 appears to be functionally redundant with a previously described gene, gld-1 (Francis, R., Barton, M. K., Kimble, J. and Schedl, T. (1995) Genetics 139, 579–606). Germ cells in gld-1(o) and gld-2 single mutants enter meiosis at the normal time, but germ cells in gld-2 gld-1(o) double mutants do not enter meiosis. Instead, the double mutant germline is mitotic throughout and forms a large tumor. We suggest that gld-1 and gld-2 define two independent regulatory pathways, each of which can be sufficient for entry into meiosis. Epistasis analyses show that gld-1 and gld-2 work downstream of the glp-1 signal transduction pathway. Therefore, we hypothesize that glp-1 promotes proliferation by inhibiting the meiosis-promoting functions of gld-1 and gld-2.

scholarly journals Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline

Development ◽  
1999 ◽  
Vol 126 (5) ◽  
pp. 1011-1022 ◽  
Author(s):  
T.L. Gumienny ◽  
E. Lambie ◽  
E. Hartwieg ◽  
H.R. Horvitz ◽  
M.O. Hengartner
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Germ Cell ◽  
Somatic Cell ◽  
Cell Fate ◽  
Germ Cells ◽  
Mapk Pathway ◽  
Apoptotic Cell ◽  
C Elegans ◽  
Pathway Activation

Development of the nematode Caenorhabditis elegans is highly reproducible and the fate of every somatic cell has been reported. We describe here a previously uncharacterized cell fate in C. elegans: we show that germ cells, which in hermaphrodites can differentiate into sperm and oocytes, also undergo apoptotic cell death. In adult hermaphrodites, over 300 germ cells die, using the same apoptotic execution machinery (ced-3, ced-4 and ced-9) as the previously described 131 somatic cell deaths. However, this machinery is activated by a distinct pathway, as loss of egl-1 function, which inhibits somatic cell death, does not affect germ cell apoptosis. Germ cell death requires ras/MAPK pathway activation and is used to maintain germline homeostasis. We suggest that apoptosis eliminates excess germ cells that acted as nurse cells to provide cytoplasmic components to maturing oocytes.

scholarly journals Multiple Genetic Pathways Involving the Caenorhabditis elegans Bloom's Syndrome Genes him-6, rad-51, and top-3 Are Needed To Maintain Genome Stability in the Germ Line

2004 ◽  
Vol 24 (11) ◽  
pp. 5016-5027 ◽  
Author(s):  
Chantal Wicky ◽  
Arno Alpi ◽  
Myriam Passannante ◽  
Ann Rose ◽  
Anton Gartner ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Germ Cells ◽  
Meiotic Recombination ◽  
Germ Line ◽  
Genetic Interaction ◽  
Double Strand Breaks ◽  
Mitotic Catastrophe ◽  
Bloom's Syndrome ◽  
Strand Breaks ◽  
Bloom’S Syndrome

ABSTRACT Bloom's syndrome (BS) is an autosomal-recessive human disorder caused by mutations in the BS RecQ helicase and is associated with loss of genomic integrity and an increased incidence of cancer. We analyzed the mitotic and the meiotic roles of Caenorhabditis elegans him-6, which we show to encode the ortholog of the human BS gene. Mutations in him-6 result in an enhanced irradiation sensitivity, a partially defective S-phase checkpoint, and in reduced levels of DNA-damage induced apoptosis. Furthermore, him-6 mutants exhibit a decreased frequency of meiotic recombination that is probably due to a defect in the progression of crossover recombination. In mitotically proliferating germ cells, our genetic interaction studies, as well as the assessment of the number of double-strand breaks via RAD-51 foci, reveal a complex regulatory network that is different from the situation in yeast. Although the number of double-strand breaks in him-6 and top-3 single mutants is elevated, the combined depletion of him-6 and top-3 leads to mitotic catastrophe concomitant with a massive increase in the level of double-strand breaks, a phenotype that is completely suppressed by rad-51. him-6 and top-3 are thus needed to maintain low levels of double-strand breaks in normally proliferating germ cells, and both act in partial redundant pathways downstream of rad-51 to prevent mitotic catastrophy. Finally, we show that topoisomerase IIIα acts independently during a late stage of meiotic recombination.

scholarly journals hecd-1 Modulates Notch Activity in Caenorhabditis elegans

2015 ◽  
Vol 5 (3) ◽  
pp. 353-359 ◽  
Author(s):  
Yunting Chen ◽  
Iva Greenwald
Keyword(s):  
Quality Control ◽  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Germ Line ◽  
Notch Pathway ◽  
Cell Fate Decisions ◽  
Notch Activity ◽  
C Elegans ◽  
Somatic Gonad ◽  
Constitutively Active

Abstract Notch is a receptor that mediates cell–cell interactions that specify binary cell fate decisions in development and tissue homeostasis. Inappropriate Notch signaling is associated with cancer, and mutations in Notch pathway components have been associated with developmental diseases and syndromes. In Caenorhabditis elegans, suppressors of phenotypes associated with constitutively active LIN-12/Notch have identified many conserved core components and direct or indirect modulators. Here, we molecularly identify sel(ar584), originally isolated as a suppressor of a constitutively active allele of lin-12. We show that sel(ar584) is an allele of hecd-1, the ortholog of human HECDT1, a ubiquitin ligase that has been implicated in several different mammalian developmental events. We studied interactions of hecd-1 with lin-12 in the somatic gonad and with the other C. elegans Notch gene, glp-1, in the germ line. We found that hecd-1 acts as a positive modulator of lin-12/Notch activity in a somatic gonad context—the original basis for its isolation—but acts autonomously as a negative modulator of glp-1/Notch activity in the germ line. As the yeast ortholog of HECD-1, Ufd4p, has been shown to function in quality control, and C. elegans  HECD-1 has been shown to affect mitochondrial maintenance, we propose that the different genetic interactions between hecd-1 and Notch genes we observed in different cell contexts may reflect differences in quality control regulatory mechanisms or in cellular metabolism.

scholarly journals The mog-1 gene is required for the switch from spermatogenesis to oogenesis in Caenorhabditis elegans.

Genetics ◽  
1993 ◽  
Vol 133 (4) ◽  
pp. 919-931 ◽  
Author(s):  
P L Graham ◽  
J Kimble
Keyword(s):  
Caenorhabditis Elegans ◽  
Sex Determination ◽  
Germ Cells ◽  
Germ Line ◽  
Loss Of Function ◽  
Wild Type ◽  
Per Se ◽  
Post Transcriptional Regulation ◽  
Germline Sex Determination ◽  
Embryonic Death

Abstract Caenorhabditis elegans hermaphrodites make first sperm, then oocytes. By contrast, animals homozygous for any of six loss-of-function mutations in the gene mog-1 (for masculinization of the germ line) make sperm continuously and do not switch into oogenesis. Therefore, in mog-1 mutants, germ cells that normally would become oocytes are transformed into sperm. By contrast, somatic sexual fates are normal, suggesting that mog-1 plays a germ line-specific role in sex determination. Analyses of double mutants suggest that mog-1 negatively regulates the fem genes and/or fog-1: mog-1; fem and mog-1; fog-1 double mutants all make oocytes rather than sperm. Therefore, we propose that wild-type mog-1 is required in the hermaphrodite germ line for regulation of the switch from spermatogenesis to oogenesis rather than for specification of oogenesis per se. In addition to its role in germline sex determination, maternal mog-1 is required for embryogenesis: most progeny of a mog-1; fem or mog-1; fog-1 mother die as embryos. How might the roles of mog-1 in the sperm/oocyte switch and embryogenesis be linked? Previous work showed that fem-3 is regulated post-transcriptionally to achieve the sperm/oocyte switch. We speculate that mog-1 may function in the post-transcriptional regulation of numerous germ-line RNAs, including fem-3. A loss of mog-1 might inappropriately activate fem-3 and thereby abolish the sperm/oocyte switch; its loss might also lead to misregulation of maternal RNAs and thus embryonic death.

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