Neuroblast proliferation: Numb-ing the tendency to differentiate
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Polo-mediated phosphorylation of Pon promotes proper subcellular localization of Numb and limits self-renewal of Drosophila neural progenitor cells.
Asymmetric cell division is mediated by the selective localization and segregation of cellular proteins into daughter cells, and is critical for the development of multi-cellular organisms. The cell fate determinant protein Numb is unequally partitioned during asymmetric cell division in Drosophila neuroblasts; the daughter cell that receives Numb tends to differentiate, while the other daughter cell remains an undifferentiated progenitor capable of self-renewal. Numb localization is achieved through binding to Pon (Partner of Numb), and the factors that influence Pon/Numb localization and function are the subject of intense investigation. In Nature, William Chia, Bingwei Lu and colleagues report that Polo phosphorylates Pon to promote correct localization of Numb and thus regulates the self-renewal of Drosophila neuroblasts.
Polo and its orthologs — Polo-like kinase (Plk) in mammals and cell division cycle 5 (Cdc5) in yeast — have important roles in cell cycle progression and cancer. Pon contains a consensus Polo phosphorylation site and the authors found that Polo was able to phosphorylate Pon both in vitro and in vivo. Polo-mediated phosphorylation of Pon was critical for its localization to the basal periphery of embryonic neuroblasts, as a Pon mutant with an alanine point mutation (PonS611A) at the consensus Polo phosphorylation site mislocalized to the apical and basal cortex. Neuroblasts expressing hypomorphic alleles of Polo were used to explore the effect of Polo-mediated Pon phosphorylation on Numb localization. Both Pon and Numb were mislocalized in these Polo-mutant cells. Exogenous expression of wild-type Pon, but not PonS611A, was able to rescue the correct localization of Numb.
Given the known role of Polo and its orthologs in oncogenesis, the authors investigated the role of Polo and Numb in neuroblast division. Expression of hypomorphic alleles of Polo resulted in a dramatic increase in the number of neuroblasts in the central brain. The increased cellular proliferation correlated with a marked decrease in neuronal differentiation, indicating that Polo functions as a potential tumor suppressor in Drosophila neuroblasts by promoting asymmetric cell division and differentiation, and limiting self-renewal. Overexpression of Numb suppressed the hyperproliferative phenotype observed in Polo-null cells. Previous studies indicated that Numb antagonizes Notch signaling; consistent with these reports, depletion of Notch also inhibited the formation of supernumerary neuroblasts in the Polo mutants.
Together, these data show that Polo-mediated phosphorylation of Pon sequesters Numb at the basal periphery of neuroblasts, which favors the accumulation of Pon/Numb in only one daughter cell. In cells that lack Polo, the diffuse localization of Numb in both daughter cells appears to limit differentiation and promote self-renewal. Future studies on the effect of Numb localization on proliferation and determination could potentially yield new clues about oncogenesis and stem-cell renewal.
Emily J. Chenette Signaling Gateway
Reference
Hongyan Wang, Yingshi Ouyang, W. Gregory Somers, William Chia & Bingwei Lu. Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon. Nature449, 96-100 (2007) | Article | PubMed |
