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First published online June 5, 2009
doi: 10.1242/10.1242/dev.035758

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Protein phosphatase 2A regulates self-renewal of Drosophila neural stem cells

¹ Neuroscience and Behavioral Disorder Program, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857.
² Temasek Life Sciences Laboratory, 1 Research Link, Singapore 117604.
³ Department of Anatomy and Cell Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria 3010, Australia.
⁴ Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857.
⁵ National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433.
⁶ Singapore Institute for Clinical Sciences, A^*STAR 138668; Duke-NUS Graduate Medical School, Singapore 169857.
⁷ Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
⁸ Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610.
⁹ Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543.

^* Author for correspondence (e-mail: Hongyan.wang{at}duke-nus.edu.sg)

Accepted 1 May 2009

Drosophila larval brain neural stem cells, also known as neuroblasts, divide asymmetrically to generate a self-renewing neuroblast and a ganglion mother cell (GMC) that divides terminally to produce two differentiated neurons or glia. Failure of asymmetric cell division can result in hyperproliferation of neuroblasts, a phenotype resembling brain tumors. Here we have identified Drosophila Protein phosphatase 2A (PP2A) as a brain tumor-suppressor that can inhibit self-renewal of neuroblasts. Supernumerary larval brain neuroblasts are generated at the expense of differentiated neurons in PP2A mutants. Neuroblast overgrowth was observed in both dorsomedial (DM)/posterior Asense-negative (PAN) neuroblast lineages and non-DM neuroblast lineages. The PP2A heterotrimeric complex, composed of the catalytic subunit (Mts), scaffold subunit (PP2A-29B) and a B-regulatory subunit (Tws), is required for the asymmetric cell division of neuroblasts. The PP2A complex regulates asymmetric localization of Numb, Pon and Atypical protein kinase C, as well as proper mitotic spindle orientation. Interestingly, PP2A and Polo kinase enhance Numb and Pon phosphorylation. PP2A, like Polo, acts to prevent excess neuroblast self-renewal primarily by regulating asymmetric localization and activation of Numb. Reduction of PP2A function in larval brains or S2 cells causes a marked decrease in Polo transcript and protein abundance. Overexpression of Polo or Numb significantly suppresses neuroblast overgrowth in PP2A mutants, suggesting that PP2A inhibits excess neuroblast self-renewal in the Polo/Numb pathway.

Key words: PP2A, Self-renewal and differentiation, Drosophila, Neural stem cell, Neuroblast, Asymmetric division

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