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Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon


Self-renewal and differentiation are cardinal features of stem cells. Asymmetric cell division provides one fundamental mechanism by which stem cell self-renewal and differentiation are balanced1,2. A failure of this balance could lead to diseases such as cancer3,4,5,6. During asymmetric division of stem cells, factors controlling their self-renewal and differentiation are unequally segregated between daughter cells. Numb is one such factor that is segregated to the differentiating daughter cell during the stem-cell-like neuroblast divisions in Drosophila melanogaster7, where it inhibits self-renewal8,9. The localization and function of Numb is cell-cycle-dependent7,10,11,12. Here we show that Polo (ref. 13), a key cell cycle regulator, the mammalian counterparts of which have been implicated as oncogenes as well as tumour suppressors14,15, acts as a tumour suppressor in the larval brain. Supernumerary neuroblasts are produced at the expense of neurons in polo mutants. Polo directly phosphorylates Partner of Numb (Pon, ref. 16), an adaptor protein for Numb, and this phosphorylation event is important for Pon to localize Numb. In polo mutants, the asymmetric localization of Pon, Numb and atypical protein kinase C are disrupted, whereas other polarity markers are largely unaffected. Overexpression of Numb suppresses neuroblast overproliferation caused by polo mutations, suggesting that Numb has a major role in mediating this effect of Polo. Our results reveal a biochemical link between the cell cycle and the asymmetric protein localization machinery, and indicate that Polo can inhibit progenitor self-renewal by regulating the localization and function of Numb.

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Figure 1: Polo phosphorylates Pon and this phosphorylation event regulates the asymmetric localization of Pon.
Figure 2: Polo functions as a tumour suppressor to inhibit neuroblast self-renewal and to promote neuronal differentiation.
Figure 3: Polo kinase is required for the asymmetric localization of Pon and Numb and for correct spindle orientation.
Figure 4: Polo controls Numb asymmetry through phosphorylation of Pon, and neuroblast self-renewal through regulation of Numb.


  1. Morrison, S. J. & Kimble, J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441, 1068–1074 (2006)

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  4. 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)

    CAS  Article  Google Scholar 

  5. 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)

    CAS  Article  Google Scholar 

  6. 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)

    CAS  Article  Google Scholar 

  7. 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)

    CAS  Article  Google Scholar 

  8. 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)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  10. Tio, M., Udolph, G., Yang, X. & Chia, W. cdc2 links the Drosophila cell cycle and asymmetric division machineries. Nature 409, 1063–1067 (2001)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  12. Zhou, Y. et al. The mammalian Golgi regulates numb signaling in asymmetric cell division by releasing ACBD3 during mitosis. Cell 129, 163–178 (2007)

    CAS  Article  Google Scholar 

  13. Sunkel, C. E. & Glover, D. M. polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J. Cell Sci. 89, 25–38 (1988)

    PubMed  Google Scholar 

  14. Barr, F. A., Sillje, H. H. & Nigg, E. A. Polo-like kinases and the orchestration of cell division. Nature Rev. Mol. Cell Biol. 5, 429–440 (2004)

    CAS  Article  Google Scholar 

  15. van de Weerdt, B. C. & Medema, R. H. Polo-like kinases: a team in control of the division. Cell Cycle 5, 853–864 (2006)

    CAS  Article  Google Scholar 

  16. 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)

    CAS  Article  Google Scholar 

  17. 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)

    CAS  Article  Google Scholar 

  18. 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  Article  Google Scholar 

  19. 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)

    CAS  Article  Google Scholar 

  20. 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)

    CAS  Article  Google Scholar 

  21. Smith, C. A. et al. aPKC-mediated phosphorylation regulates asymmetric membrane localization of the cell fate determinant Numb. EMBO J. 26, 468–480 (2007)

    CAS  Article  Google Scholar 

  22. Bhalerao, S., Berdnik, D., Torok, T. & Knoblich, J. A. Localization-dependent and -independent roles of numb contribute to cell-fate specification in Drosophila. Curr. Biol. 15, 1583–1590 (2005)

    CAS  Article  Google Scholar 

  23. Moutinho-Santos, T., Sampaio, P., Amorim, I., Costa, M. & Sunkel, C. E. In vivo localisation of the mitotic POLO kinase shows a highly dynamic association with the mitotic apparatus during early embryogenesis in Drosophila. Biol. Cell 91, 585–596 (1999)

    CAS  Article  Google Scholar 

  24. Berdnik, D. & Knoblich, J. A. Drosophila Aurora-A is required for centrosome maturation and actin-dependent asymmetric protein localization during mitosis. Curr. Biol. 12, 640–647 (2002)

    CAS  Article  Google Scholar 

  25. Choksi, S. P. et al. Prospero acts as a binary switch between self-renewal and differentiation in Drosophila neural stem cells. Dev. Cell 11, 775–789 (2006)

    CAS  Article  Google Scholar 

  26. 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  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  28. Clarke, A. S., Tang, T. T., Ooi, D. L. & Orr-Weaver, T. L. POLO kinase regulates the Drosophila centromere cohesion protein MEI-S332. Dev. Cell 8, 53–64 (2005)

    CAS  Article  Google Scholar 

  29. 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)

    ADS  CAS  Article  Google Scholar 

  30. Nishimura, I., Yang, Y. & Lu, B. PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila. Cell 116, 671–682 (2004)

    CAS  Article  Google Scholar 

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We thank D. Glover, F. Matsuzaki, Y. N. Jan, A. Wodarz, C. Doe, J. Knoblich, L. Luo, T. Orr-Weaver, C. Sunkel, B. Edgar, H. Richardson, F. Schweisguth, J. B. Skeath, A. Gould, E. D. Schejter, the Developmental Studies Hybridoma Bank and the Bloomington Stock Center for fly stocks and antibodies. We thank S. Guo for reading the manuscript, and F. Yu and members of the Lu and Chia laboratories for discussion and help. H.W. thanks U. Heberlein for support and S. G. S. Ling for technical help. This was supported by a NIH grant (B.L.) and Temasek Lifesciences Laboratory funding (W.C.)

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Correspondence to William Chia or Bingwei Lu.

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Wang, H., Ouyang, Y., Somers, W. et al. Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon. Nature 449, 96–100 (2007).

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