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Asymmetric and symmetric stem-cell divisions in development and cancer

Naturevolume 441pages10681074 (2006) | Download Citation



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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.

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  1. 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).

  2. 2

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

  3. 3

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

  4. 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).

  5. 5

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

  6. 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).

  7. 7

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

  8. 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).

  9. 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).

  10. 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).

  11. 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).

  12. 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. 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).

  14. 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).

  15. 15

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

  16. 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).

  17. 17

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

  18. 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).

  19. 19

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

  20. 20

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

  21. 21

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

  22. 22

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

  23. 23

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

  24. 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).

  25. 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).

  26. 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).

  27. 27

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

  28. 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).

  29. 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).

  30. 30

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

  31. 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).

  32. 32

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

  33. 33

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

  34. 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).

  35. 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).

  36. 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).

  37. 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).

  38. 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).

  39. 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).

  40. 40

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

  41. 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).

  42. 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).

  43. 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).

  44. 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).

  45. 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).

  46. 46

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

  47. 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).

  48. 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).

  49. 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).

  50. 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).

  51. 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).

  52. 52

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

  53. 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).

  54. 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).

  55. 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).

  56. 56

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

  57. 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).

  58. 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).

  59. 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).

  60. 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).

  61. 61

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

  62. 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).

  63. 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).

  64. 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).

  65. 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).

  66. 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).

  67. 67

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

  68. 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).

  69. 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).

  70. 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).

  71. 71

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

  72. 72

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

  73. 73

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

  74. 74

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

  75. 75

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

  76. 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).

  77. 77

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

  78. 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).

  79. 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).

  80. 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).

  81. 81

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

  82. 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).

  83. 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).

  84. 84

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

  85. 85

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

  86. 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).

  87. 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).

  88. 88

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

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

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  1. Department of Internal Medicine, Howard Hughes Medical Institute and Life Sciences Institute, and Center for Stem Cell Biology, University of Michigan, Ann Arbor, 48109-2216, Michigan, USA

    • Sean J. Morrison
  2. Howard Hughes Medical Institute and Department of Biochemistry, Laboratory of Molecular Biology and Department of Medical Genetics, University of Wisconsin-Madison, Wisconsin, 53706-1544, USA

    • Judith Kimble


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