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

Abstract

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.

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Acknowledgements

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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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). https://doi.org/10.1038/nature06056

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