title: Dickkopf 1 mediates glucocorticoid-induced changes in human neural progenitor cell proliferation and differentiation.
abstract: Glucocorticoids (GC) are critical for normal development of the fetal brain, and alterations in their levels can induce neurotoxicity with detrimental consequences. Still, there is little information available on the effects of GC on human neural stem/progenitor cells (hNPC). In the present study, we have investigated the effects of the synthetic GC dexamethasone (Dex) on hNPC grown as neurospheres, with special focus on their proliferation and differentiation capacity and the underlying molecular mechanisms. Immunocytochemical stainings showed that Dex markedly decreases proliferation and neuronal differentiation while promoting glia cell formation. Analysis of pathway-specific genes revealed that Dex induces an upregulation of the Wnt-signaling antagonist DKK1. Moreover, Dex- or DKK1-treated hNPCs showed reduced transcriptional levels of the two canonical Wnt target genes cyclin D1 and inhibitor of DNA binding 2 (ID2). Chromatin immunoprecipitation showed that Dex, via the glucocorticoid receptor, interacts with the DKK1 promotor. Treatment of hNPC with recombinant DKK1 or neutralizing antibodies indicated that DKK1 has a critical role in the Dex-induced inhibition of proliferation and neuronal differentiation with a concomitant increase in glial cells. Taken together, our findings show that GC reduce proliferation and interfere with differentiation of hNPCs via the canonical Wnt-signaling pathway.
authors: Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors: Michaela
authors: M
authors: Moors
authors: Raj
authors: R
authors: Bose
authors: Krishan
authors: K
authors: Johansson-Haque
authors: Karin
authors: K
authors: Edoff
authors: Sam
authors: S
authors: Okret
authors: Sandra
authors: S
authors: Ceccatelli
mesh_terms: D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D003907:Dexamethasone / Q000633:toxicity*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005938:Glucocorticoids / Q000633:toxicity*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D018874:Spheroids, Cellular; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: C501126:DKK1 protein, human; D005938:Glucocorticoids; D036341:Intercellular Signaling Peptides and Proteins; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone