Skip to main content
PMC home page
Genetics logoLink to Genetics
. 1995 Apr;139(4):1553–1566. doi: 10.1093/genetics/139.4.1553

Sli-1, a Negative Regulator of Let-23-Mediated Signaling in C. Elegans

G D Jongeward 1, T R Clandinin 1, P W Sternberg 1
PMCID: PMC1206484  PMID: 7789760

Abstract

By screening for suppressors of hypomorphic mutations of let-23, a receptor tyrosine kinase necessary for vulval induction in Caenorhabditis elegans, we recovered >/=12 mutations defining the sli-1 (suppressor of lineage defect) locus. sli-1 mutations suppress four of five phenotypes associated with hypomorphic alleles of let-23 but do not suppress let-23 null alleles. Thus, a sli-1 mutation does not bypass the requirement for functional let-23 but rather allows more potent LET-23-dependent signaling. Mutations at the sli-1 locus are otherwise silent with respect to vulval differentiation and cause only a low-penetrance abnormal head phenotype. Mutations at sli-1 also suppress the vulval defects but not other defects associated with mutations of sem-5, whose product likely interacts with LET-23 protein during vulval induction. Mutations at sli-1 suppress lin-2, lin-7 and lin-10 mutations but only partially suppress lin-3 and let-60 mutations and do not suppress a lin-45 mutation. The sli-1 locus displays dosage sensitivity: severe reduction of function alleles of sli-1 are semidominant suppressors; a duplication of the sli-1 (+) region enhances the vulvaless phenotype of hypomorphic mutations of let-23. We propose that sli-1 is a negative regulator that acts at or near the LET-23-mediated step of the vulval induction pathway. Our analysis suggests that let-23 can activate distinct signaling pathways in different tissues: one pathway is required for vulval induction; another pathway is involved in hermaphrodite fertilty and is not regulated by sli-1.

Full Text

The Full Text of this article is available as a PDF (3.5 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aroian R. V., Koga M., Mendel J. E., Ohshima Y., Sternberg P. W. The let-23 gene necessary for Caenorhabditis elegans vulval induction encodes a tyrosine kinase of the EGF receptor subfamily. Nature. 1990 Dec 20;348(6303):693–699. doi: 10.1038/348693a0. [DOI] [PubMed] [Google Scholar]
  2. Aroian R. V., Lesa G. M., Sternberg P. W. Mutations in the Caenorhabditis elegans let-23 EGFR-like gene define elements important for cell-type specificity and function. EMBO J. 1994 Jan 15;13(2):360–366. doi: 10.1002/j.1460-2075.1994.tb06269.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Aroian R. V., Levy A. D., Koga M., Ohshima Y., Kramer J. M., Sternberg P. W. Splicing in Caenorhabditis elegans does not require an AG at the 3' splice acceptor site. Mol Cell Biol. 1993 Jan;13(1):626–637. doi: 10.1128/mcb.13.1.626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Aroian R. V., Sternberg P. W. Multiple functions of let-23, a Caenorhabditis elegans receptor tyrosine kinase gene required for vulval induction. Genetics. 1991 Jun;128(2):251–267. doi: 10.1093/genetics/128.2.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Avery L., Horvitz H. R. A cell that dies during wild-type C. elegans development can function as a neuron in a ced-3 mutant. Cell. 1987 Dec 24;51(6):1071–1078. doi: 10.1016/0092-8674(87)90593-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Beitel G. J., Clark S. G., Horvitz H. R. Caenorhabditis elegans ras gene let-60 acts as a switch in the pathway of vulval induction. Nature. 1990 Dec 6;348(6301):503–509. doi: 10.1038/348503a0. [DOI] [PubMed] [Google Scholar]
  7. Chamberlin H. M., Sternberg P. W. Multiple cell interactions are required for fate specification during male spicule development in Caenorhabditis elegans. Development. 1993 Jun;118(2):297–324. doi: 10.1242/dev.118.2.297. [DOI] [PubMed] [Google Scholar]
  8. Chamberlin H. M., Sternberg P. W. The lin-3/let-23 pathway mediates inductive signalling during male spicule development in Caenorhabditis elegans. Development. 1994 Oct;120(10):2713–2721. doi: 10.1242/dev.120.10.2713. [DOI] [PubMed] [Google Scholar]
  9. Clark S. G., Lu X., Horvitz H. R. The Caenorhabditis elegans locus lin-15, a negative regulator of a tyrosine kinase signaling pathway, encodes two different proteins. Genetics. 1994 Aug;137(4):987–997. doi: 10.1093/genetics/137.4.987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Clark S. G., Stern M. J., Horvitz H. R. C. elegans cell-signalling gene sem-5 encodes a protein with SH2 and SH3 domains. Nature. 1992 Mar 26;356(6367):340–344. doi: 10.1038/356340a0. [DOI] [PubMed] [Google Scholar]
  11. Clark S. G., Stern M. J., Horvitz H. R. Genes involved in two Caenorhabditis elegans cell-signaling pathways. Cold Spring Harb Symp Quant Biol. 1992;57:363–373. doi: 10.1101/sqb.1992.057.01.041. [DOI] [PubMed] [Google Scholar]
  12. Cox G. N., Laufer J. S., Kusch M., Edgar R. S. Genetic and Phenotypic Characterization of Roller Mutants of CAENORHABDITIS ELEGANS. Genetics. 1980 Jun;95(2):317–339. doi: 10.1093/genetics/95.2.317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ferguson E. L., Horvitz H. R. Identification and characterization of 22 genes that affect the vulval cell lineages of the nematode Caenorhabditis elegans. Genetics. 1985 May;110(1):17–72. doi: 10.1093/genetics/110.1.17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ferguson E. L., Sternberg P. W., Horvitz H. R. A genetic pathway for the specification of the vulval cell lineages of Caenorhabditis elegans. Nature. 1987 Mar 19;326(6110):259–267. doi: 10.1038/326259a0. [DOI] [PubMed] [Google Scholar]
  15. Greenwald I. S., Horvitz H. R. unc-93(e1500): A behavioral mutant of Caenorhabditis elegans that defines a gene with a wild-type null phenotype. Genetics. 1980 Sep;96(1):147–164. doi: 10.1093/genetics/96.1.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Han M., Aroian R. V., Sternberg P. W. The let-60 locus controls the switch between vulval and nonvulval cell fates in Caenorhabditis elegans. Genetics. 1990 Dec;126(4):899–913. doi: 10.1093/genetics/126.4.899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Han M., Sternberg P. W. Analysis of dominant-negative mutations of the Caenorhabditis elegans let-60 ras gene. Genes Dev. 1991 Dec;5(12A):2188–2198. doi: 10.1101/gad.5.12a.2188. [DOI] [PubMed] [Google Scholar]
  18. Han M., Sternberg P. W. let-60, a gene that specifies cell fates during C. elegans vulval induction, encodes a ras protein. Cell. 1990 Nov 30;63(5):921–931. doi: 10.1016/0092-8674(90)90495-z. [DOI] [PubMed] [Google Scholar]
  19. Herman R. K. Crossover suppressors and balanced recessive lethals in Caenorhabditis elegans. Genetics. 1978 Jan;88(1):49–65. doi: 10.1093/genetics/88.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Herman R. K., Hedgecock E. M. Limitation of the size of the vulval primordium of Caenorhabditis elegans by lin-15 expression in surrounding hypodermis. Nature. 1990 Nov 8;348(6297):169–171. doi: 10.1038/348169a0. [DOI] [PubMed] [Google Scholar]
  21. Hill R. J., Sternberg P. W. The gene lin-3 encodes an inductive signal for vulval development in C. elegans. Nature. 1992 Aug 6;358(6386):470–476. doi: 10.1038/358470a0. [DOI] [PubMed] [Google Scholar]
  22. Hodgkin J., Papp A., Pulak R., Ambros V., Anderson P. A new kind of informational suppression in the nematode Caenorhabditis elegans. Genetics. 1989 Oct;123(2):301–313. doi: 10.1093/genetics/123.2.301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Huang L. S., Tzou P., Sternberg P. W. The lin-15 locus encodes two negative regulators of Caenorhabditis elegans vulval development. Mol Biol Cell. 1994 Apr;5(4):395–411. doi: 10.1091/mbc.5.4.395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kim S. K., Horvitz H. R. The Caenorhabditis elegans gene lin-10 is broadly expressed while required specifically for the determination of vulval cell fates. Genes Dev. 1990 Mar;4(3):357–371. doi: 10.1101/gad.4.3.357. [DOI] [PubMed] [Google Scholar]
  25. Lackner M. R., Kornfeld K., Miller L. M., Horvitz H. R., Kim S. K. A MAP kinase homolog, mpk-1, is involved in ras-mediated induction of vulval cell fates in Caenorhabditis elegans. Genes Dev. 1994 Jan;8(2):160–173. doi: 10.1101/gad.8.2.160. [DOI] [PubMed] [Google Scholar]
  26. Lee J., Jongeward G. D., Sternberg P. W. unc-101, a gene required for many aspects of Caenorhabditis elegans development and behavior, encodes a clathrin-associated protein. Genes Dev. 1994 Jan;8(1):60–73. doi: 10.1101/gad.8.1.60. [DOI] [PubMed] [Google Scholar]
  27. Lewis J. A., Hodgkin J. A. Specific neuroanatomical changes in chemosensory mutants of the nematode Caenorhabditis elegans. J Comp Neurol. 1977 Apr 1;172(3):489–510. doi: 10.1002/cne.901720306. [DOI] [PubMed] [Google Scholar]
  28. Pulak R., Anderson P. mRNA surveillance by the Caenorhabditis elegans smg genes. Genes Dev. 1993 Oct;7(10):1885–1897. doi: 10.1101/gad.7.10.1885. [DOI] [PubMed] [Google Scholar]
  29. Sigurdson D. C., Spanier G. J., Herman R. K. Caenorhabditis elegans deficiency mapping. Genetics. 1984 Oct;108(2):331–345. doi: 10.1093/genetics/108.2.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Songyang Z., Shoelson S. E., Chaudhuri M., Gish G., Pawson T., Haser W. G., King F., Roberts T., Ratnofsky S., Lechleider R. J. SH2 domains recognize specific phosphopeptide sequences. Cell. 1993 Mar 12;72(5):767–778. doi: 10.1016/0092-8674(93)90404-e. [DOI] [PubMed] [Google Scholar]
  31. Stern M. J., Marengere L. E., Daly R. J., Lowenstein E. J., Kokel M., Batzer A., Olivier P., Pawson T., Schlessinger J. The human GRB2 and Drosophila Drk genes can functionally replace the Caenorhabditis elegans cell signaling gene sem-5. Mol Biol Cell. 1993 Nov;4(11):1175–1188. doi: 10.1091/mbc.4.11.1175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sternberg P. W., Horvitz H. R. The combined action of two intercellular signaling pathways specifies three cell fates during vulval induction in C. elegans. Cell. 1989 Aug 25;58(4):679–693. doi: 10.1016/0092-8674(89)90103-7. [DOI] [PubMed] [Google Scholar]
  33. Sternberg P. W. Intercellular signaling and signal transduction in C. elegans. Annu Rev Genet. 1993;27:497–521. doi: 10.1146/annurev.ge.27.120193.002433. [DOI] [PubMed] [Google Scholar]
  34. Sulston J. E., Horvitz H. R. Abnormal cell lineages in mutants of the nematode Caenorhabditis elegans. Dev Biol. 1981 Feb;82(1):41–55. doi: 10.1016/0012-1606(81)90427-9. [DOI] [PubMed] [Google Scholar]
  35. Sulston J. E., White J. G. Regulation and cell autonomy during postembryonic development of Caenorhabditis elegans. Dev Biol. 1980 Aug;78(2):577–597. doi: 10.1016/0012-1606(80)90353-x. [DOI] [PubMed] [Google Scholar]
  36. Sulston J., Du Z., Thomas K., Wilson R., Hillier L., Staden R., Halloran N., Green P., Thierry-Mieg J., Qiu L. The C. elegans genome sequencing project: a beginning. Nature. 1992 Mar 5;356(6364):37–41. doi: 10.1038/356037a0. [DOI] [PubMed] [Google Scholar]
  37. Waterston R., Martin C., Craxton M., Huynh C., Coulson A., Hillier L., Durbin R., Green P., Shownkeen R., Halloran N. A survey of expressed genes in Caenorhabditis elegans. Nat Genet. 1992 May;1(2):114–123. doi: 10.1038/ng0592-114. [DOI] [PubMed] [Google Scholar]
  38. Wilson R., Ainscough R., Anderson K., Baynes C., Berks M., Bonfield J., Burton J., Connell M., Copsey T., Cooper J. 2.2 Mb of contiguous nucleotide sequence from chromosome III of C. elegans. Nature. 1994 Mar 3;368(6466):32–38. doi: 10.1038/368032a0. [DOI] [PubMed] [Google Scholar]
  39. Wu Y., Han M. Suppression of activated Let-60 ras protein defines a role of Caenorhabditis elegans Sur-1 MAP kinase in vulval differentiation. Genes Dev. 1994 Jan;8(2):147–159. doi: 10.1101/gad.8.2.147. [DOI] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES