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Asymmetric cell division: recent developments and their implications for tumour biology

Key Points

  • Asymmetric cell division involves the segregation of cytoplasmic determinants into one of the two daughter cells. Considerable progress has been made in understanding this important biological process during the past 10 years.

  • Cytoplasmic determinants localize asymmetrically because they are differentially modified or associate with different cytoplasmic components on the two opposing ends of a cell.

  • Centrosomes induce the break in symmetry and initiate polarization in the one-cell Caenorhabditis elegans embryo. In Drosophila melanogaster neuroblasts, centrosomes maintain polarity over multiple cell cycles.

  • α-subunits of heterotrimeric G proteins form complexes with microtubule-binding proteins to regulate microtubule–cell membrane attachment and position mitotic spindles. This determines the orientation of division and the size of daughter cells.

  • Defects in asymmetric cell division can lead to tumour formation when they occur in stem cells.

Abstract

The ability of cells to divide asymmetrically is essential for generating diverse cell types during development. The past 10 years have seen tremendous progress in our understanding of this important biological process. We have learned that localized phosphorylation events are responsible for the asymmetric segregation of cell fate determinants in mitosis and that centrosomes and microtubules play important parts in this process. The relevance of asymmetric cell division for stem cell biology has added a new dimension to the field, and exciting connections between asymmetric cell division and tumorigenesis have begun to emerge.

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Figure 1: Models for asymmetric cell division.
Figure 2: Asymmetric segregation of protein determinants.
Figure 3: Par proteins and centrosomes establish cortical polarity in Drosophila melanogaster neuroblasts.
Figure 4: Three ways to generate different daughter cell sizes.
Figure 5: Asymmetric cell division and tumour formation.

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References

  1. Conklin, E. G. The organization and cell-lineage of the ascidian egg. J. Acad. Nat. Sci. Philadelphia 13, 1–119 (1905).

    Google Scholar 

  2. Rhyu, M. S., Jan, L. Y. & Jan, Y. N. Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells. Cell 76, 477–491 (1994). This study shows for the first time that the asymmetric segregation of a cytoplasmic determinant is important for asymmetric cell division in somatic cells.

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  Google Scholar 

  4. Uemura, T., Shepherd, S., Ackerman, L., Jan, L. Y. & Jan, Y. N. numb, a gene required in determination of cell fate during sensory organ formation in Drosophila embryos. Cell 58, 349–360 (1989).

    Article  CAS  PubMed  Google Scholar 

  5. Kemphues, K. J., Priess, J. R., Morton, D. G. & Cheng, N. S. Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 52, 311–320 (1988). This study describes the identification of Par proteins, which are key regulators of asymmetric cell division and cell polarity.

    Article  CAS  PubMed  Google Scholar 

  6. Ohno, S. Intercellular junctions and cellular polarity: the PAR–aPKC complex, a conserved core cassette playing fundamental roles in cell polarity. Curr. Opin. Cell Biol. 13, 641–68 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Suzuki, A. & Ohno, S. The PAR–aPKC system: lessons in polarity. J. Cell Sci. 119, 979–987 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Etemad-Moghadam, B., Guo, S. & Kemphues, K. J. Asymmetrically distributed PAR-3 protein contributes to cell polarity and spindle alignment in early C. elegans embryos. Cell 83, 743–752 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Hung, T. J. & Kemphues, K. J. PAR-6 is a conserved PDZ domain-containing protein that colocalizes with PAR-3 in Caenorhabditis elegans embryos. Development 126, 127–135 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Tabuse, Y. et al. Atypical protein kinase C cooperates with PAR-3 to establish embryonic polarity in Caenorhabditis elegans. Development 125, 3607–3614 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Guo, S. & Kemphues, K. J. par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell 81, 611–620 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Boyd, L., Guo, S., Levitan, D., Stinchcomb, D. T. & Kemphues, K. J. PAR-2 is asymmetrically distributed and promotes association of P granules and PAR-1 with the cortex in C. elegans embryos. Development 122, 3075–3084 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Wodarz, A., Ramrath, A., Kuchinke, U. & Knust, E. Bazooka provides an apical cue for Inscuteable localization in Drosophila neuroblasts. Nature 402, 544–547 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Schober, M., Schaefer, M. & Knoblich, J. A. Bazooka recruits Inscuteable to orient asymmetric cell divisions in Drosophila neuroblasts. Nature 402, 548–551 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Petronczki, M. & Knoblich, J. A. DmPAR-6 directs epithelial polarity and asymmetric cell division of neuroblasts in Drosophila. Nature Cell Biol. 3, 43–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Wodarz, A., Ramrath, A., Grimm, A. & Knust, E. Drosophila atypical protein kinase C associates with Bazooka and controls polarity of epithelia and neuroblasts. J. Cell Biol. 150, 1361–1374 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rolls, M. M., Albertson, R., Shih, H. P., Lee, C. Y. & Doe, C. Q. Drosophila aPKC regulates cell polarity and cell proliferation in neuroblasts and epithelia. J. Cell Biol. 163, 1089–1098 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Knoblich, J. A. Asymmetric cell division during animal development. Nature Rev. Mol. Cell Biol. 2, 11–20 (2001).

    Article  CAS  Google Scholar 

  19. Ito, K. & Hotta, Y. Proliferation pattern of postembryonic neuroblasts in the brain of Drosophila melanogaster. Dev. Biol. 149, 134–148 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Bowman, S. K. et al. The tumor suppressors Brat and Numb regulate transit-amplifying neuroblast lineages in Drosophila. Dev. Cell. 14, 535–546 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Boone, J. Q. & Doe, C. Q. Identification of Drosophila type II neuroblast lineages containing transit amplifying ganglion mother cells. Dev. Neurobiol. 68, 1185–1195 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bello, B. C., Izergina, N., Caussinus, E. & Reichert, H. Amplification of neural stem cell proliferation by intermediate progenitor cells in Drosophila brain development. Neural Develop. 3, 5 (2008). Together with references 20 and 21, this article describes type II neuroblasts that generate a transit-amplifying population of intermediate neural progenitors and have become a valuable model system for stem cell biology.

    Article  PubMed Central  CAS  Google Scholar 

  23. Ito, K., Awano, W., Suzuki, K., Hiromi, Y. & Yamamoto, D. The Drosophila mushroom body is a quadruple structure of clonal units each of which contains a virtually identical set of neurones and glial cells. Development 124, 761–771 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Egger, B., Boone, J. Q., Stevens, N. R., Brand, A. H. & Doe, C. Q. Regulation of spindle orientation and neural stem cell fate in the Drosophila optic lobe. Neural Develop. 2, 1 (2007).

    Article  PubMed Central  CAS  Google Scholar 

  25. Neumüller, R. A. & Knoblich, J. A. Dividing cellular asymmetry: asymmetric cell division and its implications for stem cells and cancer. Genes Dev. 23, 2675–2699 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Knoblich, J. A. Mechanisms of asymmetric stem cell division. Cell 132, 583–597 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Wu, P. S., Egger, B. & Brand, A. H. Asymmetric stem cell division: lessons from Drosophila. Semin. Cell Dev. Biol. 19, 283–293 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Doe, C. Q. Neural stem cells: balancing self-renewal with differentiation. Development 135, 1575–1587 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Berdnik, D., Török, T., González- Gaitán, M. & Knoblich, J. A. The endocytic protein α-Adaptin is required for Numb-mediated asymmetric cell division in Drosophila. Dev. Cell 3, 221–231 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Sonoda, J. & Wharton, R. P. Drosophila Brain tumor is a translational repressor. Genes Dev. 15, 762–773 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee, C. Y., Wilkinson, B. D., Siegrist, S. E., Wharton, R. P. & Doe, C. Q. Brat is a Miranda cargo protein that promotes neuronal differentiation and inhibits neuroblast self-renewal. Dev. Cell 10, 441–449 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Bello, B., Reichert, H. & Hirth, F. The brain tumor gene negatively regulates neural progenitor cell proliferation in the larval central brain of Drosophila. Development 133, 2639–2648 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Betschinger, J., Mechtler, K. & Knoblich, J. A. Asymmetric segregation of the tumor suppressor Brat regulates self-renewal in Drosophila neural stem cells. Cell 124, 1241–1253 (2006). Together with references 31 and 32, this study shows that asymmetrically segregating determinants can act as tumour suppressors in D. melanogaster.

    Article  CAS  PubMed  Google Scholar 

  34. Lu, B., Rothenberg, M., Jan, L. Y. & Jan, Y. N. Partner of Numb colocalizes with Numb during mitosis and directs Numb asymmetric localization in Drosophila neural and muscle progenitors. Cell 95, 225–235 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Wang, H., Ouyang, Y., Somers, W. G., Chia, W. & Lu, B. Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon. Nature 449, 96–100 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Knoblich, J. A., Jan, L. Y. & Jan, Y. N. Asymmetric segregation of Numb and Prospero during cell division. Nature 377, 624–627 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Spana, E. P. & Doe, C. Q. The prospero transcription factor is asymmetrically localized to the cell cortex during neuroblast mitosis in Drosophila. Development 121, 3187–3195 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Shen, C. P., Jan, L. Y. & Jan, Y. N. Miranda is required for the asymmetric localization of Prospero during mitosis in Drosophila. Cell 90, 449–458 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Ikeshima-Kataoka, H., Skeath, J. B., Nabeshima, Y., Doe, C. Q. & Matsuzaki, F. Miranda directs Prospero to a daughter cell during Drosophila asymmetric divisions. Nature 390, 625–629 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Matsuzaki, F., Ohshiro, T., Ikeshima-Kataoka, H. & Izumi, H. Miranda localizes staufen and prospero asymmetrically in mitotic neuroblasts and epithelial cells in early Drosophila embryogenesis. Development 125, 4089–4098 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Kraut, R. & Campos-Ortega, J. A. inscuteable, a neural precursor gene of Drosophila, encodes a candidate for a cytoskeleton adaptor protein. Dev. Biol. 174, 65–81 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Kraut, R., Chia, W., Jan, L. Y., Jan, Y. N. & Knoblich, J. A. Role of inscuteable in orienting asymmetric cell divisions in Drosophila. Nature 383, 50–55 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Schaefer, M., Petronczki, M., Dorner, D., Forte, M. & Knoblich, J. A. Heterotrimeric G proteins direct two modes of asymmetric cell division in the Drosophila nervous system. Cell 107, 183–194 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Schaefer, M., Shevchenko, A., Shevchenko, A. & Knoblich, J. A. A protein complex containing Inscuteable and the Gα-binding protein Pins orients asymmetric cell divisions in Drosophila. Curr. Biol. 10, 353–362 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Yu, F., Morin, X., Cai, Y., Yang, X. & Chia, W. Analysis of partner of inscuteable, a novel player of Drosophila asymmetric divisions, reveals two distinct steps in Inscuteable apical localization. Cell 100, 399–409 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Siller, K. H., Cabernard, C. & Doe, C. Q. The NuMA-related Mud protein binds Pins and regulates spindle orientation in Drosophila neuroblasts. Nature Cell Biol. 8, 594–600 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Izumi, Y., Ohta, N., Hisata, K., Raabe, T. & Matsuzaki, F. Drosophila Pins-binding protein Mud regulates spindle-polarity coupling and centrosome organization. Nature Cell Biol. 8, 586–593 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Bowman, S. K., Neumüller, R. A., Novatchkova, M., Du, Q. & Knoblich, J. A. The Drosophila NuMA homolog Mud regulates spindle orientation in asymmetric cell division. Dev. Cell 10, 731–742 (2006). Together with references 46 and 47, this study shows that a cortical microtubule binding protein interacts with the asymmetric cell division machinery to orient the mitotic spindle in asymmetric cell division.

    Article  CAS  PubMed  Google Scholar 

  49. Gönczy, P. Mechanisms of asymmetric cell division: flies and worms pave the way. Nature Rev. Mol. Cell Biol. 9, 355–366 (2008).

    Article  CAS  Google Scholar 

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. Munro, E., Nance, J. & Priess, J. R. Cortical flows powered by asymmetrical contraction transport PAR proteins to establish and maintain anterior-posterior polarity in the early C. elegans embryo. Dev. Cell 7, 413–424 (2004). This study shows that there is anterior cortical myosin flow in C. elegans and reveals that it is crucial for Par protein localization.

    Article  CAS  PubMed  Google Scholar 

  52. Cowan, C. R. & Hyman, A. A. Centrosomes direct cell polarity independently of microtubule assembly in C. elegans embryos. Nature 431, 92–96 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Tsai, M. C. & Ahringer, J. Microtubules are involved in anterior-posterior axis formation in C. elegans embryos. J. Cell Biol. 179, 397–402 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jenkins, N., Saam, J. R. & Mango, S. E. CYK-4/GAP provides a localized cue to initiate anteroposterior polarity upon fertilization. Science 313, 1298–1301 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Zonies, S., Motegi, F., Hao, Y. & Seydoux, G. Symmetry breaking and polarization of the C. elegans zygote by the polarity protein PAR-2. Development 137, 1669–1677 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hao, Y., Boyd, L. & Seydoux, G. Stabilization of cell polarity by the C. elegans RING protein PAR-2. Dev. Cell 10, 199–208 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gönczy, P. & Rose, L. S. Asymmetric cell division and axis formation in the embryo. WormBook 15 Oct 2005 (doi:10.1895/wormbook.1.30.1).

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

    Article  CAS  PubMed  Google Scholar 

  59. Zhang, F., Barboric, M., Blackwell, T. K. & Peterlin, B. M. A model of repression: CTD analogs and PIE-1 inhibit transcriptional elongation by P-TEFb. Genes Dev. 17, 748–758 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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).

    Article  CAS  PubMed  Google Scholar 

  61. Schubert, C. M., Lin, R., de Vries, C. J., Plasterk, R. H. & Priess, J. R. MEX-5 and MEX-6 function to establish soma/germline asymmetry in early C. elegans embryos. Mol. Cell 5, 671–682 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Draper, B. W., Mello, C. C., Bowerman, B., Hardin, J. & Priess, J. R. MEX-3 is a KH domain protein that regulates blastomere identity in early C. elegans embryos. Cell 87, 205–216 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Cuenca, A. A., Schetter, A., Aceto, D., Kemphues, K. & Seydoux, G. Polarization of the C. elegans zygote proceeds via distinct establishment and maintenance phases. Development 130, 1255–1265 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Broadus, J. & Doe, C. Q. Extrinsic cues, intrinsic cues and microfilaments regulate asymmetric protein localization in Drosophila neuroblasts. Curr. Biol. 7, 827–835 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Knoblich, J. A., Jan, L. Y. & Jan, Y. N. The N terminus of the Drosophila Numb protein directs membrane association and actin-dependent asymmetric localization. Proc. Natl Acad. Sci. USA 94, 13005–13010 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Shen, C. P. et al. Miranda as a multidomain adapter linking apically localized Inscuteable and basally localized Staufen and Prospero during asymmetric cell division in Drosophila. Genes Dev. 12, 1837–1846 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jan, Y. N. & Jan, L. Y. Asymmetric cell division in the Drosophila nervous system. Nature Rev. Neurosci. 2, 772–779 (2001).

    Article  CAS  Google Scholar 

  68. Petritsch, C., Tavosanis, G., Turck, C. W., Jan, L. Y. & Jan, Y. N. The Drosophila myosin VI jaguar is required for basal protein targeting and correct spindle orientation in mitotic neuroblasts. Dev. Cell 4, 273–281 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Ohshiro, T., Yagami, T., Zhang, C. & Matsuzaki, F. Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature 408, 593–596 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Peng, C. Y., Manning, L., Albertson, R. & Doe, C. Q. The tumour-suppressor genes lgl and dlg regulate basal protein targeting in Drosophila neuroblasts. Nature 408, 596–600 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Strand, D. et al. The Drosophila lethal(2)giant larvae tumor suppressor protein forms homo-oligomers and is associated with nonmuscle myosin II heavy chain. J. Cell Biol. 127, 1361–1373 (1994).

    Article  CAS  PubMed  Google Scholar 

  72. Strand, D., Raska, I. & Mechler, B. M. The Drosophila lethal(2)giant larvae tumor suppressor protein is a component of the cytoskeleton. J. Cell Biol. 127, 1345–1360 (1994).

    Article  CAS  PubMed  Google Scholar 

  73. Betschinger, J., Mechtler, K. & Knoblich, J. A. The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 422, 326–330 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Betschinger, J., Eisenhaber, F. & Knoblich, J. A. Phosphorylation-induced autoinhibition regulates the cytoskeletal protein Lethal (2) giant larvae. Curr. Biol. 15, 276–282 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Barros, C. S., Phelps, C. B. & Brand, A. H. Drosophila nonmuscle myosin II promotes the asymmetric segregation of cell fate determinants by cortical exclusion rather than active transport. Dev. Cell 5, 829–840 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Wirtz-Peitz, F., Nishimura, T. & Knoblich, J. A. Linking cell cycle to asymmetric division: Aurora-A phosphorylates the Par complex to regulate Numb localization. Cell 135, 161–173 (2008). This study connects the phosphorylation of segregating determinants to the cell cycle machinery and provides a model for how determinants localize asymmetrically during mitosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cabernard, C., Prehoda, K. E. & Doe, C. Q. A spindle-independent cleavage furrow positioning pathway. Nature 467, 91–94 (2010). This paper identifies an unprecedented pathway for cytokinesis that involves asymmetric cortical localization of myosin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Atwood, S. X. & Prehoda, K. E. aPKC phosphorylates Miranda to polarize fate determinants during neuroblast asymmetric cell division. Curr. Biol. 19, 723–729 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lu, B., Ackerman, L., Jan, L. Y. & Jan, Y. N. Modes of protein movement that lead to the asymmetric localization of partner of Numb during Drosophila neuroblast division. Mol. Cell 4, 883–891 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Mayer, B., Emery, G., Berdnik, D., Wirtz-Peitz, F. & Knoblich, J. A. Quantitative analysis of protein dynamics during asymmetric cell division. Curr. Biol. 15, 1847–1854 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Smith, C. A. et al. aPKC-mediated phosphorylation regulates asymmetric membrane localization of the cell fate determinant Numb. EMBO J. 26, 468–480 (2007). This investigation shows that phosphorylation of the segregating determinant Numb by the asymmetrically localized kinase aPKC regulates membrane association and provides a model for how Numb localizes asymmetrically in mitosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yamanaka, T. et al. Mammalian Lgl forms a protein complex with PAR-6 and aPKC independently of PAR-3 to regulate epithelial cell polarity. Curr. Biol. 13, 734–743 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Skwarek, L. C., Garroni, M. K., Commisso, C. & Boulianne, G. L. Neuralized contains a phosphoinositide-binding motif required downstream of ubiquitination for Delta endocytosis and Notch signaling. Dev. Cell 13, 783–795 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Cabernard, C. & Doe, C. Q. Apical/basal spindle orientation is required for neuroblast homeostasis and neuronal differentiation in Drosophila. Dev. Cell 17, 134–141 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Siegrist, S. E. & Doe, C. Q. Microtubule-induced cortical cell polarity. Genes Dev. 21, 483–496 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Siegrist, S. E. & Doe, C. Q. Microtubule-induced Pins/Gαi cortical polarity in Drosophila neuroblasts. Cell 123, 1323–1335 (2005). This article provides a molecular explanation for the telophase rescue pathway that acts during anaphase and telophase.

    Article  CAS  PubMed  Google Scholar 

  87. DeRenzo, C., Reese, K. J. & Seydoux, G. Exclusion of germ plasm proteins from somatic lineages by cullin-dependent degradation. Nature 424, 685–689 (2003). This work shows that protein degradation is important for asymmetric localization of cytoplasmic determinants in C. elegans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Daniels, B. R., Perkins, E. M., Dobrowsky, T. M., Sun, S. X. & Wirtz, D. Asymmetric enrichment of PIE-1 in the Caenorhabditis elegans zygote mediated by binary counterdiffusion. J. Cell Biol. 184, 473–479 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Tenlen, J. R., Molk, J. N., London, N., Page, B. D. & Priess, J. R. MEX-5 asymmetry in one-cell C. elegans embryos requires PAR-4- and PAR-1-dependent phosphorylation. Development 135, 3665–3675 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Daniels, B. R., Dobrowsky, T. M., Perkins, E. M., Sun, S. X. & Wirtz, D. MEX-5 enrichment in the C. elegans early embryo mediated by differential diffusion. Development 137, 2579–2585 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Turing, A. M. The chemical basis of morphogenesis. Phil. Trans. R. Soc. Lond. B 237, 37–72 (1952).

    Article  Google Scholar 

  92. Kondo, S. The reaction-diffusion system: a mechanism for autonomous pattern formation in the animal skin. Genes Cells 7, 535–541 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. 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).

    Article  CAS  PubMed  Google Scholar 

  94. Rebollo, E., Roldán, M. & Gonzalez, C. Spindle alignment is achieved without rotation after the first cell cycle in Drosophila embryonic neuroblasts. Development 136, 3393–3397 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Rebollo, E. et al. Functionally unequal centrosomes drive spindle orientation in asymmetrically dividing Drosophila neural stem cells. Dev. Cell 12, 467–474 (2007). This study reveals how mitotic spindle orientation is established in D. melanogaster larval neuroblasts.

    Article  CAS  PubMed  Google Scholar 

  96. Januschke, J. & Gonzalez, C. The interphase microtubule aster is a determinant of asymmetric division orientation in Drosophila neuroblasts. J. Cell Biol. 188, 693–706 (2010). This paper shows how spindle orientation is kept constant over many divisions in D. melanogaster neuroblasts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Spradling, A. C. & Zheng, Y. Developmental biology. The mother of all stem cells? Science 315, 469–470 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Wang, X. et al. Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature 461, 947–955 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Gotta, M., Dong, Y., Peterson, Y. K., Lanier, S. M. & Ahringer, J. Asymmetrically distributed C. elegans homologs of AGS3/PINS control spindle position in the early embryo. Curr. Biol. 13, 1029–1037 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Colombo, K. et al. Translation of polarity cues into asymmetric spindle positioning in Caenorhabditis elegans embryos. Science 300, 1957–1961 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Srinivasan, D. G., Fisk, R. M., Xu, H. & Van Den Heuvel, S. A complex of LIN-5 and GPR proteins regulates G protein signaling and spindle function in C. elegans. Genes Dev. (2003).

  102. Nguyen-Ngoc, T., Afshar, K. & Gönczy, P. Coupling of cortical dynein and Gα proteins mediates spindle positioning in Caenorhabditis elegans. Nature Cell Biol. 9, 1294–1302 (2007). This study reveals how cortical polarity proteins connect to microtubules to position the mitotic spindle in C. elegans.

    Article  CAS  PubMed  Google Scholar 

  103. Ou, G., Stuurman, N., D'Ambrosio, M. & Vale, R. D. Polarized myosin produces unequal-size daughters during asymmetric cell division. Science 330, 667–680 (2010).

    Article  CAS  Google Scholar 

  104. Gateff, E. Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 200, 1448–1459 (1978).

    Article  CAS  PubMed  Google Scholar 

  105. Gateff, E. Tumor suppressor and overgrowth suppressor genes of Drosophila melanogaster: developmental aspects. Int. J. Dev. Biol. 38, 565–590 (1994).

    CAS  PubMed  Google Scholar 

  106. Lee, C. Y., Robinson, K. J. & Doe, C. Q. Lgl, Pins and aPKC regulate neuroblast self-renewal versus differentiation. Nature 439, 594–598 (2006). This study shows that mutations in genes regulating asymmetric cell division can cause overproliferation in the D. melanogaster brain.

    Article  CAS  PubMed  Google Scholar 

  107. Lee, C. Y. et al. Drosophila Aurora-A kinase inhibits neuroblast self-renewal by regulating aPKC/Numb cortical polarity and spindle orientation. Genes Dev. 20, 3464–3474 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wang, H. et al. Aurora-A acts as a tumor suppressor and regulates self-renewal of Drosophila neuroblasts. Genes Dev. 20, 3453–3463 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kitajima, A., Fuse, N., Isshiki, T. & Matsuzaki, F. Progenitor properties of symmetrically dividing Drosophila neuroblasts during embryonic and larval development. Dev. Biol. 347, 9–23 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Basto, R. et al. Centrosome amplification can initiate tumorigenesis in flies. Cell 133, 1032–1042 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Castellanos, E., Dominguez, P. & Gonzalez, C. Centrosome dysfunction in Drosophila neural stem cells causes tumors that are not due to genome instability. Curr. Biol. 18, 1209–1214 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Caussinus, E. & Gonzalez, C. Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nature Genet. 37, 1125–1129 (2005). This article shows that defects in asymmetric cell division cause the formation of tumours on transplantation of defective stem cells in D. melanogaster.

    Article  CAS  PubMed  Google Scholar 

  113. Maurange, C., Cheng, L. & Gould, A. P. Temporal transcription factors and their targets schedule the end of neural proliferation in Drosophila. Cell 133, 891–902 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Bello, B. C., Hirth, F. & Gould, A. P. A pulse of the Drosophila Hox protein Abdominal-A schedules the end of neural proliferation via neuroblast apoptosis. Neuron 37, 209–219 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Siegrist, S. E., Haque, N. S., Chen, C. H., Hay, B. A. & Hariharan, I. K. Inactivation of both foxo and reaper promotes long-term adult neurogenesis in Drosophila. Curr. Biol. 20, 643–648 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  117. Cicalese, A. et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138, 1083–1095 (2009). This paper connects tumour formation in breast cancer with defects in asymmetric cell division.

    Article  CAS  PubMed  Google Scholar 

  118. Wu, M. et al. Imaging hematopoietic precursor division in real time. Cell Stem Cell 1, 541–554 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shinin, V., Gayraud-Morel, B., Gomes, D. & Tajbakhsh, S. Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nature Cell Biol. 8, 677–682 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Quyn, A. J. et al. Spindle orientation bias in gut epithelial stem cell compartments is lost in precancerous tissue. Cell Stem Cell 6, 175–181 (2010).

    Article  CAS  PubMed  Google Scholar 

  122. Costa, M. R., Wen, G., Lepier, A., Schroeder, T. & Götz, M. Par-complex proteins promote proliferative progenitor divisions in the developing mouse cerebral cortex. Development 135, 11–22 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Rasin, M. R. et al. Numb and Numbl are required for maintenance of cadherin-based adhesion and polarity of neural progenitors. Nature Neurosci. 10, 819–827 (2007). This study changes our view of how mammalian homologues act during asymmetric cell division in the mouse brain.

    Article  CAS  PubMed  Google Scholar 

  124. Kosodo, Y. et al. Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. EMBO J. 23, 2314–2324 (2004). This study provides important insight into the mechanism of asymmetric cell division in the mouse brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Dontu, G. et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17, 1253–1270 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Colaluca, I. N. et al. NUMB controls p53 tumour suppressor activity. Nature 451, 76–80 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ito, T. et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 466, 765–768 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Dietzl, G. et al. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448, 151–156 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Mummery-Widmer, J. L. et al. Genome-wide analysis of Notch signalling in Drosophila by transgenic RNAi. Nature 458, 987–992 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Shendure, J. & Ji, H. Next-generation DNA sequencing. Nature Biotech. 26, 1135–1145 (2008).

    Article  CAS  Google Scholar 

  132. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).

    Article  CAS  PubMed  Google Scholar 

  133. Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730–737 (1997).

    Article  CAS  PubMed  Google Scholar 

  134. Singh, S. K. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821–5828 (2003).

    CAS  PubMed  Google Scholar 

  135. Dick, J. E. Breast cancer stem cells revealed. Proc. Natl Acad. Sci. USA 100, 3547–3549 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lobo, N. A., Shimono, Y., Qian, D. & Clarke, M. F. The biology of cancer stem cells. Annu. Rev. Cell Dev. Biol. 23, 675–699 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Rosen, J. M. & Jordan, C. T. The increasing complexity of the cancer stem cell paradigm. Science 324, 1670–1673 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Kwon, C. H. et al. Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res. 68, 3286–3294 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Siller, K. H. & Doe, C. Q. Spindle orientation during asymmetric cell division. Nature Cell Biol. 11, 365–374 (2009).

    Article  CAS  PubMed  Google Scholar 

  141. Santolini, E. et al. Numb is an endocytic protein. J. Cell Biol. 151, 1345–152 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Götz, M. & Huttner, W. B. The cell biology of neurogenesis. Nature Rev. Mol. Cell Biol. 6, 777–788 (2005).

    Article  CAS  Google Scholar 

  143. Bultje, R. S. et al. Mammalian Par3 regulates progenitor cell asymmetric division via notch signaling in the developing neocortex. Neuron 63, 189–202 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Miyata, T., Kawaguchi, A., Okano, H. & Ogawa, M. Asymmetric inheritance of radial glial fibers by cortical neurons. Neuron 31, 727–741 (2001).

    Article  CAS  PubMed  Google Scholar 

  145. Schwamborn, J. C., Berezikov, E. & Knoblich, J. A. The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors. Cell 136, 913–925 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank all the members of my laboratory for fruitful and stimulating discussions. My laboratory is funded by the Austrian Academy of Science, the Austrian Science Fund (FWF), The European Research Council (ERC) and the European Union Seventh Framework Programme grant EuroSyStem.

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Glossary

Centrosome

(Also called the microtubule-organizing centre or spindle pole). A structure that nucleates microtubules and is important for signalling processes.

Neuroblast

A D. melanogaster neural progenitor cell that generates all of the neurons and glial cells in the brain.

Mushroom body

A mushroom-shaped paired-neuropil structure that is found in the D. melanogaster brain and functions in learning and memory.

Optic lobe

A morphologically distinct part of the developing D. melanogaster brain that forms the visual processing centres.

Blastomere

A cell that is generated during embryonic cleavage divisions.

P granule

A type of ribonucleoprotein particle that segregates with and marks all cells of the C. elegans germ line.

Centriole

A small organelle (consisting of two short, barrel-like arrays of microtubules) that organizes the centrosome and contributes to cytokinesis and cell-cycle progression.

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Knoblich, J. Asymmetric cell division: recent developments and their implications for tumour biology. Nat Rev Mol Cell Biol 11, 849–860 (2010). https://doi.org/10.1038/nrm3010

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