title: A switch from canonical to noncanonical Wnt signaling mediates early differentiation of human neural stem cells.
abstract: Wnt/β-catenin signaling is essential for neurogenesis but less is known about β-catenin-independent Wnt signals. We show here that Wnt/activator protein-1 (AP-1) signaling drives differentiation of human embryonic stem cell and induced pluripotent stem cell-derived neural progenitor cells. Neuronal differentiation was accompanied by a reduction in β-catenin/Tcf-dependent transcription and target gene expression, increased levels and/or phosphorylation of activating transcription factor 2 (ATF2), cyclic AMP response element-binding protein, and c-Jun, and increased AP-1-dependent transcription. Inhibition of Wnt secretion using the porcupine inhibitors IWP-2 and Wnt-C59 blocked neuronal differentiation, while activation or inhibition of Wnt/β-catenin signaling had no effect. Neuronal differentiation increased expression of several Wnt genes, including WNT3A, silencing of which reduced differentiation. Addition of recombinant Wnt-3a to cells treated with IWP-2 or Wnt-C59 increased AP-1 levels and restored neuronal differentiation. The effects of Wnt-3a could not be blocked by addition of Dkk-1 or IWR-1, suggesting the involvement of noncanonical signaling. Consistent with this, restoration of neuronal differentiation by Wnt-3a was reduced by inhibition of Jun N-terminal kinase (JNK) and by gene silencing of ATF2. Together, these observations suggest that β-catenin-independent Wnt signals promote neural stem/progenitor cell differentiation in a signaling pathway involving Wnt-3a, JNK, and ATF2.
authors.affiliation: Cell Biology and Stem Cells Unit, CIC bioGUNE, Derio, Spain.
authors.forename: Nora
authors.initials: N
authors.lastname: Bengoa-Vergniory
authors.forename: Irantzu
authors.initials: I
authors.lastname: Gorroño-Etxebarria
authors.forename: Itxaso
authors.initials: I
authors.lastname: González-Salazar
authors.forename: Robert M
authors.initials: RM
authors.lastname: Kypta
mesh_terms: D002454:Cell Differentiation / Q000502:physiology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D018808:Transcription Factor AP-1; D051153:Wnt Proteins; D051176:beta Catenin
keywords: Cell signaling; Neural differentiation; Neural stem cell; Signal transduction