Skip to main content
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2003 Aug 29;358(1436):1359–1362. doi: 10.1098/rstb.2003.1333

Regulation of the mitosis/meiosis decision in the Caenorhabditis elegans germline.

Sarah L Crittenden 1, Christian R Eckmann 1, Liaoteng Wang 1, David S Bernstein 1, Marvin Wickens 1, Judith Kimble 1
PMCID: PMC1693240  PMID: 14511482

Abstract

During the development of multicellular organisms, the processes of growth and differentiation are kept in balance to generate and maintain tissues and organs of the correct size, shape and cellular composition. We have investigated the molecular controls of growth and differentiation in the Caenorhabditis elegans germline. A single somatic cell, called the distal tip cell, promotes mitotic proliferation in the adjacent germline by GLP-1/Notch signalling. Within the germline, the decisions between mitosis and meiosis and between spermatogenesis and oogenesis are controlled by a group of conserved RNA regulators. FBF, a member of the PUF (for Pumilio and FBF) family of RNA-binding proteins, promotes mitosis by repressing gld-1 mRNA activity; the GLD-1, GLD-2, GLD-3 and NOS-3 proteins promote entry into meiosis by regulating mRNAs that remain unknown. The regulatory balance between opposing FBF and GLD activities is crucial for controlling the extent of germline proliferation. PUF proteins regulate germline stem cells in both Drosophila and C. elegans and are localized to germline stem cells of the mammalian testis. Therefore, this post-transcriptional regulatory switch may be an ancient mechanism for controlling maintenance of stem cells versus differentiation.

Full Text

The Full Text of this article is available as a PDF (164.8 KB).

Selected References

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

  1. Baonza A., Garcia-Bellido A. Notch signaling directly controls cell proliferation in the Drosophila wing disc. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2609–2614. doi: 10.1073/pnas.040576497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Berry L. W., Westlund B., Schedl T. Germ-line tumor formation caused by activation of glp-1, a Caenorhabditis elegans member of the Notch family of receptors. Development. 1997 Feb;124(4):925–936. doi: 10.1242/dev.124.4.925. [DOI] [PubMed] [Google Scholar]
  3. Christensen S., Kodoyianni V., Bosenberg M., Friedman L., Kimble J. lag-1, a gene required for lin-12 and glp-1 signaling in Caenorhabditis elegans, is homologous to human CBF1 and Drosophila Su(H). Development. 1996 May;122(5):1373–1383. doi: 10.1242/dev.122.5.1373. [DOI] [PubMed] [Google Scholar]
  4. Conboy Irina M., Rando Thomas A. The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev Cell. 2002 Sep;3(3):397–409. doi: 10.1016/s1534-5807(02)00254-x. [DOI] [PubMed] [Google Scholar]
  5. Crittenden S. L., Troemel E. R., Evans T. C., Kimble J. GLP-1 is localized to the mitotic region of the C. elegans germ line. Development. 1994 Oct;120(10):2901–2911. doi: 10.1242/dev.120.10.2901. [DOI] [PubMed] [Google Scholar]
  6. Crittenden Sarah L., Bernstein David S., Bachorik Jennifer L., Thompson Beth E., Gallegos Maria, Petcherski Andrei G., Moulder Gary, Barstead Robert, Wickens Marvin, Kimble Judith. A conserved RNA-binding protein controls germline stem cells in Caenorhabditis elegans. Nature. 2002 May 22;417(6889):660–663. doi: 10.1038/nature754. [DOI] [PubMed] [Google Scholar]
  7. Eckmann Christian R., Kraemer Brian, Wickens Marvin, Kimble Judith. GLD-3, a bicaudal-C homolog that inhibits FBF to control germline sex determination in C. elegans. Dev Cell. 2002 Nov;3(5):697–710. doi: 10.1016/s1534-5807(02)00322-2. [DOI] [PubMed] [Google Scholar]
  8. Forbes A., Lehmann R. Nanos and Pumilio have critical roles in the development and function of Drosophila germline stem cells. Development. 1998 Feb;125(4):679–690. doi: 10.1242/dev.125.4.679. [DOI] [PubMed] [Google Scholar]
  9. Francis R., Barton M. K., Kimble J., Schedl T. gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans. Genetics. 1995 Feb;139(2):579–606. doi: 10.1093/genetics/139.2.579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Henderson S. T., Gao D., Christensen S., Kimble J. Functional domains of LAG-2, a putative signaling ligand for LIN-12 and GLP-1 receptors in Caenorhabditis elegans. Mol Biol Cell. 1997 Sep;8(9):1751–1762. doi: 10.1091/mbc.8.9.1751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Henderson S. T., Gao D., Lambie E. J., Kimble J. lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans. Development. 1994 Oct;120(10):2913–2924. doi: 10.1242/dev.120.10.2913. [DOI] [PubMed] [Google Scholar]
  12. Jan E., Motzny C. K., Graves L. E., Goodwin E. B. The STAR protein, GLD-1, is a translational regulator of sexual identity in Caenorhabditis elegans. EMBO J. 1999 Jan 4;18(1):258–269. doi: 10.1093/emboj/18.1.258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jones A. R., Schedl T. 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. 1995 Jun 15;9(12):1491–1504. doi: 10.1101/gad.9.12.1491. [DOI] [PubMed] [Google Scholar]
  14. Kadyk L. C., Kimble J. Genetic regulation of entry into meiosis in Caenorhabditis elegans. Development. 1998 May;125(10):1803–1813. doi: 10.1242/dev.125.10.1803. [DOI] [PubMed] [Google Scholar]
  15. Kennedy B. K., Gotta M., Sinclair D. A., Mills K., McNabb D. S., Murthy M., Pak S. M., Laroche T., Gasser S. M., Guarente L. Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Cell. 1997 May 2;89(3):381–391. doi: 10.1016/s0092-8674(00)80219-6. [DOI] [PubMed] [Google Scholar]
  16. Kimble J. E., White J. G. On the control of germ cell development in Caenorhabditis elegans. Dev Biol. 1981 Jan 30;81(2):208–219. doi: 10.1016/0012-1606(81)90284-0. [DOI] [PubMed] [Google Scholar]
  17. Kimble J., Simpson P. The LIN-12/Notch signaling pathway and its regulation. Annu Rev Cell Dev Biol. 1997;13:333–361. doi: 10.1146/annurev.cellbio.13.1.333. [DOI] [PubMed] [Google Scholar]
  18. Kipreos E. T., Gohel S. P., Hedgecock E. M. The C. elegans F-box/WD-repeat protein LIN-23 functions to limit cell division during development. Development. 2000 Dec;127(23):5071–5082. doi: 10.1242/dev.127.23.5071. [DOI] [PubMed] [Google Scholar]
  19. Kodoyianni V., Maine E. M., Kimble J. Molecular basis of loss-of-function mutations in the glp-1 gene of Caenorhabditis elegans. Mol Biol Cell. 1992 Nov;3(11):1199–1213. doi: 10.1091/mbc.3.11.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kraemer B., Crittenden S., Gallegos M., Moulder G., Barstead R., Kimble J., Wickens M. NANOS-3 and FBF proteins physically interact to control the sperm-oocyte switch in Caenorhabditis elegans. Curr Biol. 1999 Sep 23;9(18):1009–1018. doi: 10.1016/s0960-9822(99)80449-7. [DOI] [PubMed] [Google Scholar]
  21. Lai Eric C. Keeping a good pathway down: transcriptional repression of Notch pathway target genes by CSL proteins. EMBO Rep. 2002 Sep;3(9):840–845. doi: 10.1093/embo-reports/kvf170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lee M. H., Schedl T. Identification of in vivo mRNA targets of GLD-1, a maxi-KH motif containing protein required for C. elegans germ cell development. Genes Dev. 2001 Sep 15;15(18):2408–2420. doi: 10.1101/gad.915901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lin H., Spradling A. C. A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary. Development. 1997 Jun;124(12):2463–2476. doi: 10.1242/dev.124.12.2463. [DOI] [PubMed] [Google Scholar]
  24. Lin Haifan. The stem-cell niche theory: lessons from flies. Nat Rev Genet. 2002 Dec;3(12):931–940. doi: 10.1038/nrg952. [DOI] [PubMed] [Google Scholar]
  25. Marin Veronica A., Evans Thomas C. Translational repression of a C. elegans Notch mRNA by the STAR/KH domain protein GLD-1. Development. 2003 Jun;130(12):2623–2632. doi: 10.1242/dev.00486. [DOI] [PubMed] [Google Scholar]
  26. Marshman Emma, Booth Catherine, Potten Christopher S. The intestinal epithelial stem cell. Bioessays. 2002 Jan;24(1):91–98. doi: 10.1002/bies.10028. [DOI] [PubMed] [Google Scholar]
  27. Moore Frederick L., Jaruzelska Jadwiga, Fox Mark S., Urano Jun, Firpo Meri T., Turek Paul J., Dorfman David M., Pera Renee A. Reijo. Human Pumilio-2 is expressed in embryonic stem cells and germ cells and interacts with DAZ (Deleted in AZoospermia) and DAZ-like proteins. Proc Natl Acad Sci U S A. 2003 Jan 2;100(2):538–543. doi: 10.1073/pnas.0234478100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Petcherski A. G., Kimble J. LAG-3 is a putative transcriptional activator in the C. elegans Notch pathway. Nature. 2000 May 18;405(6784):364–368. doi: 10.1038/35012645. [DOI] [PubMed] [Google Scholar]
  29. Petcherski A. G., Kimble J. Mastermind is a putative activator for Notch. Curr Biol. 2000 Jun 29;10(13):R471–R473. doi: 10.1016/s0960-9822(00)00577-7. [DOI] [PubMed] [Google Scholar]
  30. Souza G. M., da Silva A. M., Kuspa A. Starvation promotes Dictyostelium development by relieving PufA inhibition of PKA translation through the YakA kinase pathway. Development. 1999 Jun;126(14):3263–3274. doi: 10.1242/dev.126.14.3263. [DOI] [PubMed] [Google Scholar]
  31. Varnum-Finney B., Xu L., Brashem-Stein C., Nourigat C., Flowers D., Bakkour S., Pear W. S., Bernstein I. D. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med. 2000 Nov;6(11):1278–1281. doi: 10.1038/81390. [DOI] [PubMed] [Google Scholar]
  32. Wang Liaoteng, Eckmann Christian R., Kadyk Lisa C., Wickens Marvin, Kimble Judith. A regulatory cytoplasmic poly(A) polymerase in Caenorhabditis elegans. Nature. 2002 Sep 19;419(6904):312–316. doi: 10.1038/nature01039. [DOI] [PubMed] [Google Scholar]
  33. Watt F. M., Hogan B. L. Out of Eden: stem cells and their niches. Science. 2000 Feb 25;287(5457):1427–1430. doi: 10.1126/science.287.5457.1427. [DOI] [PubMed] [Google Scholar]
  34. Zhang B., Gallegos M., Puoti A., Durkin E., Fields S., Kimble J., Wickens M. P. A conserved RNA-binding protein that regulates sexual fates in the C. elegans hermaphrodite germ line. Nature. 1997 Dec 4;390(6659):477–484. doi: 10.1038/37297. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES