A Switch From Canonical to Noncanonical Wnt Signaling Mediates Early Differentiation of Human Neural Stem Cells. (26th November 2014)

• Record Type: Journal Article
• Authors: Bengoa-Vergniory, Nora; Gorroño-Etxebarria, Irantzu; González-Salazar, Itxaso; Kypta, Robert M.
• Is Part Of: Stem cells. Volume 32:Number 12(2014:Dec.)
• Page Start: 3196
• Page End: 3208
• Publication Date: 2014-11-26
• Subjects: Neural stem cell -- Neural differentiation -- Signal transduction -- Cell signaling; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.1807
• Languages: English
• ISSNs: 1066-5099

Abstract

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. Stem Cells 2014;32:3196–3208