Mechanism of Cdo-induced Wnt suppression during neuronal differentication

 

Development of the central nervous system (CNS) requires cooperation of multiple signaling pathways in regulation of cell commitment, proliferation and differentiation. Wnt and Shh signalling are reported to play critical roles in the development of CNS. Jeong et al. found that Wnt signaling is negatively regulated by Cdo, a Shh multifunctional co-receptor which is highly expressed in the CNS. The article was published on Nature Communications, recently.

 

In several types of Cdo-deficient cells, Wnt signalling was enhanced by strongly induced Wnt co-receptors,Lrp6, causing impaired neuronal differentiation. In addition, in dorsal forebrain of Cdo-deficient mice, increased cell proliferation and elevated expression levels of Wnt targets, Pax6, Gli3, and Axin2. Further investigation revealed a functional interaction between Cdo and Lrp6: they interacted to form complexes via the second Ig domain of Cdo and the LDLR domains of Lrp6. These results indicated that Cdo suppress Wnt signalling, leading to a promotion of neuron cell differentiation, and proved a direct interaction between these two signalling pathways.

 

Reference:
Nat Commun. 2014 Nov 19;5:5455.

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S1180	XAV-939	XAV-939 (NVP-XAV939) selectively inhibits Wnt/β-catenin-mediated transcription through tankyrase1/2 inhibition with IC50 of 11 nM/4 nM in cell-free assays, regulates axin levels and does not affect CRE, NF-κB or TGF-β.

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