Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Asymmetric and symmetric stem-cell divisions in development and cancer

Abstract

Listen to an interview with Sean Morrison on the stem cells podcast

Much has been made of the idea that asymmetric cell division is a defining characteristic of stem cells that enables them to simultaneously perpetuate themselves (self-renew) and generate differentiated progeny. Yet many stem cells can divide symmetrically, particularly when they are expanding in number during development or after injury. Thus, asymmetric division is not necessary for stem-cell identity but rather is a tool that stem cells can use to maintain appropriate numbers of progeny. The facultative use of symmetric or asymmetric divisions by stem cells may be a key adaptation that is crucial for adult regenerative capacity.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Stem-cell strategies.
Figure 2: Controls of asymmetric stem-cell division.
Figure 3: Symmetric divisions in the developing C. elegans germ line.
Figure 4: Symmetric stem-cell divisions in the adult germ line.
Figure 5: Stem cells can facultatively use both symmetric and asymmetric divisions.

References

  1. Betschinger, J. & Knoblich, J. A. Dare to be different: asymmetric cell division in Drosophila, C. elegans and vertebrates. Curr. Biol. 14, R674–R685 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Clevers, H. Stem cells, asymmetric division and cancer. Nature Genet. 37, 1027–1028 (2005).

    CAS  PubMed  Google Scholar 

  3. Doe, C. Q. & Bowerman, B. Asymmetric cell division: fly neuroblast meets worm zygote. Curr. Opin. Cell Biol. 13, 68–75 (2001).

    CAS  PubMed  Google Scholar 

  4. Yamashita, Y. M., Fuller, M. T. & Jones, D. L. Signaling in stem cell niches: lessons from the Drosophila germline. J. Cell Sci. 118, 665–672 (2005).

    CAS  PubMed  Google Scholar 

  5. Kimble, J. E. & White, J. G. On the control of germ cell development in Caenorhabditis elegans. Dev. Biol. 81, 208–219 (1981).

    CAS  PubMed  Google Scholar 

  6. Morrison, S. J., Hemmati, H. D., Wandycz, A. M. & Weissman, I. L. The purification and characterization of fetal liver hematopoietic stem cells. Proc. Natl Acad. Sci. USA 92, 10302–10306 (1995).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lechler, T. & Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wright, D. E. et al. Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood 97, 2278–2285 (2001).

    CAS  PubMed  Google Scholar 

  9. Morrison, S. J., Wright, D. & Weissman, I. L. Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. Proc. Natl Acad. Sci. USA 94, 1908–1913 (1997).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bodine, D., Seidel, N. E. & Orlic, D. Bone marrow collected 14 days after in vivo administration of granulocyte colony-stimulating factor and stem cell factor to mice has 10-fold more repopulating ability than untreated bone marrow. Blood 88, 89–97 (1996).

    CAS  PubMed  Google Scholar 

  11. Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36, 1021–1034 (2002).

    CAS  PubMed  Google Scholar 

  12. 12. Gö nczy, P. & Rose, L. S. Asymmetric cell division and axis formation in the embryo. In WormBook (ed. The C. elegans Research Community); published online 15 October 2005 (doi/10.1895/wormbook.1.30.1).

  13. Strome, S. & Wood, W. B. Generation of asymmetry and segregation of germ-line granules in early C. elegans embryos. Cell 35, 15–25 (1983).

    CAS  PubMed  Google Scholar 

  14. Mello, C. C., Draper, B. W., Krause, M., Weintraub, H. & Priess, J. R. The pie-1 and mex-1 genes and maternal control of blastomere identity in early C. elegans embryos. Cell 70, 163–176 (1992).

    CAS  PubMed  Google Scholar 

  15. Mello, C. C. et al. The PIE-1 protein and germline specification in C. elegans embryos. Nature 382, 710–712 (1996).

    ADS  CAS  PubMed  Google Scholar 

  16. Reese, K. J., Dunn, M. A., Waddle, J. A. & Seydoux, G. Asymmetric segregation of PIE-1 in C. elegans is mediated by two complementary mechanisms that act through separate PIE-1 protein domains. Mol. Cell 6, 445–455 (2000).

    CAS  PubMed  Google Scholar 

  17. Wodarz, A. Molecular control of cell polarity and asymmetric cell division in Drosophila neuroblasts. Curr. Opin. Cell Biol. 17, 475–481 (2005).

    CAS  PubMed  Google Scholar 

  18. Spana, E. P., Kopczynski, C., Goodman, C. S. & Doe, C. Q. Asymmetric localization of numb autonomously determines sibling neuron identity in the Drosophila CNS. Development 121, 3489–3494 (1995).

    CAS  PubMed  Google Scholar 

  19. Xie, T. & Spradling, A. C. A niche maintaining germ line stem cells in the Drosophila ovary. Science 290, 328–330 (2000).

    ADS  CAS  PubMed  Google Scholar 

  20. Spradling, A., Drummond-Barbosa, D. & Kai, T. Stem cells find their niche. Nature 414, 98–104 (2001).

    ADS  CAS  PubMed  Google Scholar 

  21. Schofield, R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4, 7–25 (1978).

    CAS  PubMed  Google Scholar 

  22. Li, L. & Xie, T. Stem cell niche: structure and function. Annu. Rev. Cell Dev. Biol. 21, 605–631 (2005).

    CAS  PubMed  Google Scholar 

  23. Tulina, N. & Matunis, E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK–STAT signaling. Science 294, 2546–2549 (2001).

    ADS  CAS  PubMed  Google Scholar 

  24. Kiger, A. A., Jones, D. L., Schulz, C., Rogers, M. B. & Fuller, M. T. Stem cell self-renewal specified by JAK–STAT activation in response to a support cell cue. Science 294, 2542–2545 (2001).

    ADS  CAS  PubMed  Google Scholar 

  25. Chen, D. & McKearin, D. Dpp signaling silences bam transcription directly to establish asymmetric divisions of germline stem cells. Curr. Biol. 13, 1786–1791 (2003).

    CAS  PubMed  Google Scholar 

  26. Song, X. et al. Bmp signals from niche cells directly repress transcription of a differentiation-promoting gene, bag of marbles, in germline stem cells in the Drosophila ovary. Development 131, 1353–1364 (2004).

    CAS  PubMed  Google Scholar 

  27. Ohlstein, B. & McKearin, D. Ectopic expression of the Drosophila Bam protein eliminates oogenic germline stem cells. Development 124, 3651–3662 (1997).

    CAS  PubMed  Google Scholar 

  28. Song, X., Zhu, C. H., Doan, C. & Xie, T. Germline stem cells anchored by adherens junctions in the Drosophila ovary niches. Science 296, 1855–1857 (2002).

    ADS  CAS  PubMed  Google Scholar 

  29. Yamashita, Y. M., Jones, D. L. & Fuller, M. T. Orientation of asymmetric stem cell divisions by the APC tumor suppressor and centrosome. Science 301, 1547–1550 (2003).

    ADS  CAS  PubMed  Google Scholar 

  30. Goldstein, B. & Hird, S. N. Specification of the anteroposterior axis in Caenorhabditis elegans. Development 122, 1467–1474 (1996).

    CAS  PubMed  Google Scholar 

  31. Cowan, C. R. & Hyman, A. A. Asymmetric cell division in C. elegans: cortical polarity and spindle positioning. Annu. Rev. Cell Dev. Biol. 20, 427–453 (2004).

    CAS  PubMed  Google Scholar 

  32. Siegrist, S. E. & Doe, C. Q. Extrinsic cues orient the cell division axis in Drosophila embryonic neuroblasts. Development 133, 529–536 (2006).

    CAS  PubMed  Google Scholar 

  33. Cayouette, M. & Raff, M. Asymmetric segregation of Numb: a mechanism for neural specification from Drosophila to mammals. Nature Neurosci. 5, 1265–1269 (2002).

    CAS  PubMed  Google Scholar 

  34. Zhong, W., Jiang, M. M., Weinmaster, G., Jan, L. Y. & Jan, Y. N. Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis. Development 124, 1887–1897 (1997).

    CAS  PubMed  Google Scholar 

  35. Zhong, W., Feder, J. N., Jiang, M. M., Jan, L. Y. & Jan, Y. N. Asymmetric localization of a mammalian numb homolog during mouse cortical neurogenesis. Neuron 17, 43–53 (1996).

    CAS  PubMed  Google Scholar 

  36. Shen, Q., Zhong, W., Jan, Y. N. & Temple, S. Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development 129, 4843–4853 (2002).

    CAS  PubMed  Google Scholar 

  37. Wakamatsu, Y., Maynard, T. M., Jones, S. U. & Weston, J. A. NUMB localizes in the basal cortex of mitotic avian neuroepithelial cells and modulates neuronal differentiation by binding to NOTCH-1. Neuron 23, 71–81 (1999).

    CAS  PubMed  Google Scholar 

  38. Verdi, J. M. et al. Distinct human NUMB isoforms regulate differentiation vs. proliferation in the neuronal lineage. Proc. Natl Acad. Sci. USA 96, 10472–10476 (1999).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Conboy, I. M. & Rando, T. A. The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev. Cell 3, 397–409 (2002).

    CAS  PubMed  Google Scholar 

  40. Chenn, A. & McConnell, S. K. Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell 82, 631–641 (1995).

    CAS  PubMed  Google Scholar 

  41. Kaltschmidt, J. A., Davidson, C. M., Brown, N. H. & Brand, A. H. Rotation and asymmetry of the mitotic spindle direct asymmetric cell division in the developing central nervous system. Nature Cell Biol. 2, 7–12 (2000).

    CAS  PubMed  Google Scholar 

  42. Lee, C. -Y., Robinson, K. J. & Doe, C. Q. Lgl, Pins and aPKC regulate neuroblast self-renewal versus differentiation. Nature 439, 594–598 (2006).

    ADS  CAS  PubMed  Google Scholar 

  43. Kimble, J. & Crittenden, S. Germline proliferation and its control. In WormBook (ed. The C. elegans Research Community); published online 15 August 2005 (doi/10.1895/wormbook.1.13.1).

    Google Scholar 

  44. Xie, T. & Spradling, A. C. decapentaplegic is essential for the maintenance and division of germline stem cells in the Drosophila ovary. Cell 94, 251–260 (1998).

    CAS  PubMed  Google Scholar 

  45. Decotto, E. & Spradling, A. C. The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals. Dev. Cell 9, 501–510 (2005).

    CAS  PubMed  Google Scholar 

  46. Kimble, J. & Hirsh, D. The postembryonic cell lineages of the hermaphrodite and male gonads in Caenorhabditis elegans. Dev. Biol. 70, 396–417 (1979).

    CAS  PubMed  Google Scholar 

  47. Feng, H. et al. CUL-2 is required for the G1-to-S phase transition and mitotic chromosome condensation in Caenorhabditis elegans. Nature Cell Biol. 1, 486–492 (1999).

    CAS  PubMed  Google Scholar 

  48. 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 127, 5071–5082 (2000).

    CAS  PubMed  Google Scholar 

  49. Kidd, A. R., Miskowski, J. A., Siegfried, K. R., Sawa, H. & Kimble, J. A β-catenin identified by functional rather than sequence criteria and its role in Wnt/MAPK signaling. Cell 121, 761–772 (2005).

    CAS  PubMed  Google Scholar 

  50. Kostic, I., Li, S. & Roy, R. cki-1 links cell division and cell fate acquisition in the C. elegans somatic gonad. Dev. Biol. 263, 242–252 (2003).

    CAS  PubMed  Google Scholar 

  51. Lam, N., Chesney, M. A. & Kimble, J. Wnt signaling and CEH-22/tinman/Nkx2.5 specify a stem cell niche in C. elegans. Curr. Biol. 16, 287–295 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kai, T. & Spradling, A. Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature 428, 564–569 (2004).

    ADS  CAS  PubMed  Google Scholar 

  53. Noctor, S. C., Martinez-Cerdeno, V., Ivic, L. & Kriegstein, A. R. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nature Neurosci. 7, 136–144 (2004).

    CAS  PubMed  Google Scholar 

  54. Huttner, W. B. & Kosodo, Y. Symmetric versus asymmetric cell division during neurogenesis in the developing vertebrate central nervous system. Curr. Opin. Cell Biol. 17, 648–657 (2005).

    CAS  PubMed  Google Scholar 

  55. Deng, W. & Lin, H. Spectrosomes and fusomes anchor mitotic spindles during asymmetric germ cell divisions and facilitate the formation of a polarized microtubule array for oocyte specification in Drosophila. Dev. Biol. 189, 79–94 (1997).

    CAS  PubMed  Google Scholar 

  56. Brawley, C. & Matunis, E. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 304, 1331–1334 (2004).

    ADS  CAS  PubMed  Google Scholar 

  57. 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 120, 2901–2911 (1994).

    CAS  PubMed  Google Scholar 

  58. Crittenden, S. L., Leonhard, K. A., Byrd, D. T. & Kimble, J. Cellular analyses of the mitotic region in the Caenorhabditis elegans adult germ line. Mol. Biol. Cell 17, 3051–3061 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Jones, A. R., Francis, R. & Schedl, T. GLD-1, a cytoplasmic protein essential for oocyte differentiation, shows stage- and sex-specific expression during Caenorhabditis elegans germline development. Dev. Biol. 180, 165–183 (1996).

    CAS  PubMed  Google Scholar 

  60. Eckmann, C. R., Crittenden, S. L., Suh, N. & Kimble, J. GLD-3 and control of the mitosis/meiosis decision in the germline of Caenorhabditis elegans. Genetics 168, 147–160 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Seery, J. P. & Watt, F. M. Asymmetric stem-cell divisions define the architecture of human oesophageal epithelium. Curr. Biol. 10, 1447–1450 (2000).

    CAS  PubMed  Google Scholar 

  62. Cheshier, S., Morrison, S. J., Liao, X. & Weissman, I. L. In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc. Natl Acad. Sci. USA 96, 3120–3125 (1999).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  63. Morshead, C. M. et al. Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13, 1071–1082 (1994).

    CAS  PubMed  Google Scholar 

  64. Zhang, R. et al. Stroke transiently increases subventricular zone cell division from asymmetric to symmetric and increases neuronal differentiation in the adult rat. J. Neurosci. 24, 5810–5815 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Reid, C. B., Tavazoie, S. F. & Walsh, C. A. Clonal dispersion and evidence for asymmetric cell division in ferret cortex. Development 124, 2441–2450 (1997).

    CAS  PubMed  Google Scholar 

  66. Morshead, C. M., Craig, C. G. & van der Kooy, D. In vivo clonal analyses reveal the properties of endogenous neural stem cell proliferation in the adult mammalian forebrain. Development 125, 2251–2261 (1998).

    CAS  PubMed  Google Scholar 

  67. Davis, A. A. & Temple, S. A self-renewing multipotential stem cell in embryonic rat cerebral cortex. Nature 372, 263–266 (1994).

    ADS  CAS  PubMed  Google Scholar 

  68. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999).

    CAS  PubMed  Google Scholar 

  69. Kiel, M. J., Yilmaz, O. H., Iwashita, T., Terhorst, C. & Morrison, S. J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

    CAS  PubMed  Google Scholar 

  70. Albertson, R. & Doe, C. Q. Dlg, Scrib and Lgl regulate neuroblast cell size and mitotic spindle asymmetry. Nature Cell Biol. 5, 166–170 (2003).

    CAS  PubMed  Google Scholar 

  71. Caussinus, E. & Gonzalez, C. Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nature Genet. 37, 1125–1129 (2005).

    CAS  PubMed  Google Scholar 

  72. Humbert, P., Russell, S. & Richardson, H. Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer. BioEssays 25, 542–553 (2003).

    CAS  PubMed  Google Scholar 

  73. Joslyn, G. et al. Identification of deletion mutations and three new genes at the familial polyposis locus. Cell 66, 601–613 (1991).

    CAS  PubMed  Google Scholar 

  74. Groden, J. et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66, 589–600 (1991).

    CAS  PubMed  Google Scholar 

  75. Kinzler, K. W. et al. Identification of FAP locus genes from chromosome 5q21. Science 253, 661–665 (1991).

    ADS  CAS  PubMed  Google Scholar 

  76. van de Wetering, M. et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241–250 (2002).

    CAS  PubMed  Google Scholar 

  77. Kuphal, S. et al. Expression of Hugl-1 is strongly reduced in malignant melanoma. Oncogene 25, 103–110 (2006).

    CAS  PubMed  Google Scholar 

  78. Schimanski, C. C. et al. Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer. Oncogene 24, 3100–3109 (2005).

    CAS  PubMed  Google Scholar 

  79. Klezovitch, O., Fernandez, T. E., Tapscott, S. J. & Vasioukhin, V. Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice. Genes Dev. 18, 559–571 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Pece, S. et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J. Cell Biol. 167, 215–221 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Stylianou, S., Clarke, R. B. & Brennan, K. Aberrant activation of notch signaling in human breast cancer. Cancer Res. 66, 1517–1525 (2006).

    CAS  PubMed  Google Scholar 

  82. Regala, R. P. et al. Atypical protein kinase Ciota plays a critical role in human lung cancer cell growth and tumorigenicity. J. Biol. Chem. 280, 31109–31115 (2005).

    CAS  PubMed  Google Scholar 

  83. Regala, R. P. et al. Atypical protein kinase C iota is an oncogene in human non-small cell lung cancer. Cancer Res. 65, 8905–8911 (2005).

    CAS  PubMed  Google Scholar 

  84. McDermott, K. M. et al. p16INK4a prevents centrosome dysfunction and genomic instability in primary cells. PLoS Biol 4, e51 (2006).

    PubMed  PubMed Central  Google Scholar 

  85. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    ADS  CAS  PubMed  Google Scholar 

  86. Pardal, R., Clarke, M. F. & Morrison, S. J. Applying the principles of stem-cell biology to cancer. Nature Rev. Cancer 3, 895–902 (2003).

    CAS  Google Scholar 

  87. 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 120, 2913–2924 (1994).

    CAS  PubMed  Google Scholar 

  88. Kadyk, L. C. & Kimble, J. Genetic regulation of entry into meiosis in Caenorhabditis elegans. Development 125, 1803–1813 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank C.-Y. Lee, Y. Yamashita, T. Lechler and A. Helsley for critically reviewing drafts of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Sean J. Morrison or Judith Kimble.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Morrison, S., Kimble, J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441, 1068–1074 (2006). https://doi.org/10.1038/nature04956

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04956

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing