title: Chemical genetics reveals a complex functional ground state of neural stem cells.
abstract: 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 cancer. 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 biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, 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.
authors.affiliation: 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.
authors.forename: Phedias
authors.initials: P
authors.lastname: Diamandis
authors.forename: Jan
authors.initials: J
authors.lastname: Wildenhain
authors.forename: Ian D
authors.initials: ID
authors.lastname: Clarke
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Sacher
authors.forename: Jeremy
authors.initials: J
authors.lastname: Graham
authors.forename: David S
authors.initials: DS
authors.lastname: Bellows
authors.forename: Erick K M
authors.initials: EK
authors.lastname: Ling
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Ward
authors.forename: Leanne G
authors.initials: LG
authors.lastname: Jamieson
authors.forename: Mike
authors.initials: M
authors.lastname: Tyers
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dirks
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000737:chemistry; D012680:Sensitivity and Specificity; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations