Journal
STEM CELLS
Volume 32, Issue 12, Pages 3196-3208Publisher
WILEY
DOI: 10.1002/stem.1807
Keywords
Neural stem cell; Neural differentiation; Signal transduction; Cell signaling
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Funding
- Basque Department of Education [BFI-2010-129]
- Spanish Ministry of Science and Innovation [SAF2011-30494]
- Department of Industry, Tourism and Trade (Etortek)
- Department of Innovation Technology of the Government of the Autonomous Community of the Basque Country
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Wnt/-catenin signaling is essential for neurogenesis but less is known about -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 -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/-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 -catenin-independent Wnt signals promote neural stem/progenitor cell differentiation in a signaling pathway involving Wnt-3a, JNK, and ATF2. Stem Cells2014;32:3196-3208
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