title: A chemical genomics screen to discover genes that modulate neural stem cell differentiation.
abstract: The authors designed a chemical genomics screen with the aim of understanding genes and pathways that modulate neural stem/precursor cell differentiation. Multipotent mouse neural precursor cells isolated from cortices of embryonic day 12 (E12) embryos were subjected to spontaneous differentiation triggered by growth factor withdrawal. A quantitative whole-well immunofluorescence assay was set up to screen tool compound sets to identify small molecules with potent, dose-dependent, and reproducible effects on increasing neural stem cell differentiation toward neuronal lineage. Among the pro-neuronal compounds, kinase inhibitors were shown to exert pro-neuronal effect via a signaling pathway associated with the kinase. The global effect of hit compounds on modulating neuronal differentiation was confirmed by an in vivo mouse study and human neural stem cells culture. This study demonstrates that a phenotypic assay using cell type-specific antibody markers can be used for a large-scale compound screen to discover targets and pathways with impacts on differentiation of lineage-restricted precursor cells toward specific lineages.
authors.affiliation: Discovery Technology, GlaxoSmithKline (China) R&D Co., Ltd. Shanghai, PR China.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Kim
authors.forename: Jamie
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Xu
authors.forename: Sharon
authors.initials: S
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Qin
authors.forename: Fenglan
authors.initials: F
authors.lastname: Wu
authors.forename: Ailian
authors.initials: A
authors.lastname: Liu
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Haiyan
authors.initials: H
authors.lastname: Fang
authors.forename: Mary
authors.initials: M
authors.lastname: Zhu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019085:Fluorescent Antibody Technique, Direct / Q000379:methods; D023281:Genomics / Q000379:methods*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction
chemical_list: D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3