Bengoa-Vergniory, N. 1 , Gorroño-Etxebarria, I. 1 , González Salazar , I. 1 & Kypta, R. 1, 2
1 Cell Biology and Stem Cells Unit, CIC bioGUNE, Derio, Bizkaia, Spain
2 Department of Surgery and Cancer, Imperial College London, UK
Wnt/beta-catenin signaling is implicated in the regulation of neural stem cell proliferation and differentiation but less is known about beta-catenin-independent Wnt signals. We show here that Wnt/AP-1 signaling, rather than Wnt/beta-catenin signaling, drives differentiation of hES and iPS cell-derived neural progenitor cells. Neuronal differentiation was accompanied by increased expression of Wnt genes, increased levels and/or phosphorylation of the AP-1 family proteins and AP-1-dependent transcription and reduced beta-catenin/Tcf-dependent transcription and target gene expression. Inhibition of Wnt secretion using porcupine inhibitors blocked neuronal differentiation, while activation or inhibition of Wnt/beta-catenin signaling had no effect. Recombinant Wnt-3a increased AP-1 protein levels and restored neuronal differentiation in cells treated with porcupine inhibitors. Restoration of neuronal differentiation was unaffected by inhibition of Wnt/beta-catenin signaling, but was reduced by inhibition of Jun N-terminal kinase and gene silencing of an AP-1 family member. Together, these results indicate that Wnt signals promote differentiation of hES and iPS cell-derived neural progenitor cells independently of beta-catenin, in a non canonical Wnt signalling pathway involving AP-1.