title: GSK3β, but not GSK3α, inhibits the neuronal differentiation of neural progenitor cells as a downstream target of mammalian target of rapamycin complex1.
abstract: Glycogen synthase kinase 3 (GSK3) acts as an important regulator during the proliferation and differentiation of neural progenitor cells (NPCs), but the roles of the isoforms of this molecule (GSK3α and GSK3β) have not been clearly defined. In this study, we investigated the functions of GSK3α and GSK3β in the context of neuronal differentiation of murine NPCs. Treatment of primary NPCs with a GSK3 inhibitor (SB216763) resulted in an increase in the percentage of TuJ1-positive immature neurons, suggesting an inhibitory role of GSK3 in embryonic neurogenesis. Downregulation of GSK3β expression increased the percentage of TuJ1-positive cells, while knock-down of GSK3α seemed to have no effect. When primary NPCs were engineered to stably express either isoform of GSK3 using retroviral vectors, GSK3β, but not GSK3α, inhibited neuronal differentiation and helped the cells to maintain the characteristics of NPCs. Mutant GSK3β (Y216F) failed to suppress neuronal differentiation, indicating that the kinase activity of GSK3β is important for this regulatory function. Similar results were obtained in vivo when a retroviral vector expressing GSK3β was delivered to E9.5 mouse brains using the ultrasound image-guided gene delivery technique. In addition, SB216763 was found to block the rapamycin-mediated inhibition of neuronal differentiation of NPCs. Taken together, our results demonstrate that GSK3β, but not GSK3α, negatively controls the neuronal differentiation of progenitor cells and that GSK3β may act downstream of the mammalian target of rapamycin complex1 signaling pathway.
authors.affiliation: 1 School of Biological Sciences, Seoul National University , Seoul, Korea.
authors.forename: Jyhyun
authors.initials: J
authors.lastname: Ahn
authors.forename: Jiwon
authors.initials: J
authors.lastname: Jang
authors.forename: Jinyong
authors.initials: J
authors.lastname: Choi
authors.forename: Junsub
authors.initials: J
authors.lastname: Lee
authors.forename: Seo-Ho
authors.initials: SH
authors.lastname: Oh
authors.forename: Junghun
authors.initials: J
authors.lastname: Lee
authors.forename: Keejung
authors.initials: K
authors.lastname: Yoon
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Kim
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: D007211:Indoles; D008301:Maleimides; D046912:Multiprotein Complexes; C417521:SB 216763; D014404:Tubulin; C462941:beta3 tubulin, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3