Journal
MOLECULAR NEUROBIOLOGY
Volume 54, Issue 8, Pages 6213-6224Publisher
HUMANA PRESS INC
DOI: 10.1007/s12035-016-0151-5
Keywords
Wnt signaling pathways; Neural stem cells
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Funding
- Spanish Ministry of Education and Science [SAF2014-51966-R, IJCI-2014-21255]
- Government of the Autonomous Community of the Basque Country Departments of Education, Industry, Tourism and Trade (Elkartek)
- Government of the Autonomous Community of the Basque Country Departments of Education and Innovation Technology
- MRC [MR/P007058/1] Funding Source: UKRI
- Medical Research Council [MR/P007058/1] Funding Source: researchfish
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Wnt proteins preferentially activate either beta-catenin-dependent or beta-catenin-independent signals, but the activity of a particular Wnt also depends on cellular context and receptor availability. We previously reported that Wnt-3a induces neural differentiation of human embryonic stem cell-derived neural stem cells (NSCs) in a beta-catenin-independent manner by activating a signal involving JNK and the AP-1 family member ATF-2. Here, we report the results of a gene silencing approach to identify the Wnt receptors that mediate this response to Wnt-3a. Silencing of ROR2 increased neuronal differentiation, as measured by expression of the genes DCX, NEUROD1, and NGN1, suggesting ROR2 signals normally prevent differentiation. Silencing of the other Wnt receptors singly did not affect Wnt-3a-induced neuronal differentiation. However, pairwise silencing of ROR1 and FZD4 or FZD5 and of LRP6 and FZD4 or FZD5 inhibited neuronal differentiation, as detected by reductions in the expression of neuronal genes and immunocytochemical detection of DCX, NEUROD1 and DCX. Ectopic expression of these receptors in HEK 293 cells increased ATF2-dependent transcription. In addition, ROR1 coimmunoprecipitated with FZD4 and LRP6 in transfected HEK 293 cells and colocalized
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