Letter abstract
Nature Chemical Biology 3, 268 - 273 (2007)
Published online: 8 April 2007 | doi:10.1038/nchembio873
Chemical genetics reveals a complex functional ground state of neural stem cells
Phedias Diamandis1,2,3,4, Jan Wildenhain4, Ian D Clarke1,2, Adrian G Sacher1,2, Jeremy Graham1,2, David S Bellows3, Erick K M Ling1,2,5, Ryan J Ward1,2,5, Leanne G Jamieson1,2,5, Mike Tyers3,4 & Peter B Dirks1,2,5,6
The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer1, 2, 3. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology4, 5, 6, 7, 8, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation8, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.
- The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto M5G 1X8, Canada.
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto M5G 1X8, Canada.
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada.
- Department of Medical Genetics and Microbiology, University of Toronto, 1 Kings College Circle, Toronto M5S 1A8, Canada.
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Banting Institute, 100 College Street, Toronto M5G 1L5, Canada.
- Division of Neurosurgery, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto M5G 1X8, Canada.
Correspondence to: Mike Tyers3,4 e-mail: tyers@mshri.on.ca
Correspondence to: Peter B Dirks1,2,5,6 e-mail: peter.dirks@sickkids.ca
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