title: Inhibition of glycogen synthase kinase-3 enhances the differentiation and reduces the proliferation of adult human olfactory epithelium neural precursors.
abstract: The olfactory epithelium (OE) contains neural precursor cells which can be easily harvested from a minimally invasive nasal biopsy, making them a valuable cell source to study human neural cell lineages in health and disease. Glycogen synthase kinase-3 (GSK-3) has been implicated in the etiology and treatment of neuropsychiatric disorders and also in the regulation of murine neural precursor cell fate in vitro and in vivo. In this study, we examined the impact of decreased GSK-3 activity on the fate of adult human OE neural precursors in vitro. GSK-3 inhibition was achieved using ATP-competitive (6-bromoindirubin-3'-oxime and CHIR99021) or substrate-competitive (TAT-eIF2B) inhibitors to eliminate potential confounding effects on cell fate due to off-target kinase inhibition. GSK-3 inhibitors decreased the number of neural precursor cells in OE cell cultures through a reduction in proliferation. Decreased proliferation was not associated with a reduction in cell survival but was accompanied by a reduction in nestin expression and a substantial increase in the expression of the neuronal differentiation markers MAP1B and neurofilament (NF-M) after 10 days in culture. Taken together, these results suggest that GSK-3 inhibition promotes the early stages of neuronal differentiation in cultures of adult human neural precursors and provide insights into the mechanisms by which alterations in GSK-3 signaling affect adult human neurogenesis, a cellular process strongly suspected to play a role in the etiology of neuropsychiatric disorders.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Aziza P
authors.initials: AP
authors.lastname: Manceur
authors.forename: Michael
authors.initials: M
authors.lastname: Tseng
authors.forename: Tamara
authors.initials: T
authors.lastname: Holowacz
authors.forename: Ian
authors.initials: I
authors.lastname: Witterick
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Richard D
authors.initials: RD
authors.lastname: McCurdy
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Warsh
authors.forename: Julie
authors.initials: J
authors.lastname: Audet
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009831:Olfactory Mucosa / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D009832:Olfactory Nerve / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D038362:Glycogen Synthase Kinase 3