Polo Playing with Numb

Abstract

The asymmetric distribution of various factors during cell division is one mechanism that enables stem cells both to renew their own population and to give rise to cells that continue to differentiate. In the asymmetric division of stem cell-like neuroblasts in Drosophila , Numb, which inhibits self-renewal, is segregated to the cell destined to differentiate. Numb segregation depends on its interaction with Partner of Numb (Pon), which becomes asymmetrically localized during mitosis. Noting that the Pon localization domain (Pon-LD) contains a serine residue (Ser 611 ) that is a potential phosphorylation site for Polo, a serine/threonine kinase involved in orchestration of the cell cycle, Wang et al . determined that Ser 611 could be phosphorylated by a mammalian Polo-like kinase in vitro. Western and immunohistochemical analyses of wild-type flies compared with flies with polo loss-of-function alleles indicated that Polo phosphorylated Ser 611 in the larval fly brain in vivo. Visualization of wild-type and phospho-mutant forms of fluorescently tagged Pon-LDs implicated Ser 611 phosphorylation in regulating Pon localization during the cell cycle. The brains of larvae with hypomorphic polo alleles contained increased numbers of neuroblasts 96 hours after hatching compared with those of wild-type larvae--a phenotype that was suppressed by Numb overexpression--and fewer neuronally differentiated cells. Moreover, Pon and Numb were missegregated in the brains of the polo mutants. Segregation of atypical protein kinase C (aPKC) was also disrupted, as was mitotic spindle orientation, whereas localization of most other asymmetrically localized proteins was not. Thus, Polo provides a link between the cell cycle and the asymmetric localization of Numb and a mechanism to inhibit neuroblast self-renewal. H. Wang, Y. Ouyang, W. G. Somers, W. Chia, B. Lu, Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon. Nature 449 , 96-100 (2007). [PubMed]