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PMID: 17417631 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Chemical genetics reveals a complex functional ground state of neural stem cells.

Nature chemical biology ·Vol. 3 ·No. 5 ·2007-05-00 ·Pages 268-73

Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, Ling EK, Ward RJ, Jamieson LG, Tyers M, Dirks PB

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.

MeSH Terms

Animals Cell Survival/drug effects Cells, Cultured Mice Molecular Structure Neoplasms/genetics,metabolism,pathology Neurons/cytology,drug effects,metabolism Pharmaceutical Preparations/chemistry Sensitivity and Specificity Stem Cells/cytology,drug effects,metabolism

Chemicals

Pharmaceutical Preparations

Authors & Affiliations

11 authors, click to expand affiliations / ORCID

Diamandis Phedias

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.

Wildenhain Jan

Clarke Ian D

Sacher Adrian G

Graham Jeremy

Bellows David S

Ling Erick K M

Ward Ryan J

Jamieson Leanne G

Tyers Mike

Dirks Peter B

Article Info

Journal

Nature chemical biology

Abbr.

Nat Chem Biol

ISSN

1552-4450

DOI

10.1038/nchembio873

Published

2007-05-00

Epub

2007-00-08

Pages

268-73

Language

English

Region

United States

NLM ID

101231976

Subset

Databases

PubChem-Substance

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Corrections

CommentIn

PMID: 17438546

CommentIn

PMID: 17637767

External Links

PubMed source DOI: 10.1038/nchembio873 View journal details

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Chemical genetics reveals a complex functional ground state of neural stem cells.

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