Abstract
Activation of Wnt signaling enhances self-renewal of mouse embryonic and neural stem/progenitor cells. In contrast, undifferentiated ES cells show a very low level of endogenous Wnt signaling, and ectopic activation of Wnt signaling has been shown to block neuronal differentiation. Therefore, it remains unclear whether or not endogenous Wnt/β-catenin signaling is necessary for self-renewal or neuronal differentiation of ES cells. To investigate this, we examined the expression profiles of Wnt signaling components. Expression levels of Wnts known to induce β-catenin were very low in undifferentiated ES cells. Stable ES cell lines which can monitor endogenous activity of Wnt/β-catenin signaling suggest that Wnt signaling was very low in undifferentiated ES cells, whereas it increased during embryonic body formation or neuronal differentiation. Interestingly, application of small molecules which can positively (BIO, GSK3β inhibitor) or negatively (IWR-1-endo, Axin stabilizer) control Wnt/β-catenin signaling suggests that activation of that signaling at different time periods had differential effects on neuronal differentiation of 46C ES cells. Further, ChIP analysis suggested that β-catenin/TCF1 complex directly regulated the expression of Sox1 during neuronal differentiation. Overall, our data suggest that Wnt/β-catenin signaling plays differential roles at different time points of neuronal differentiation.
Highlights
Embryonic stem (ES) cells are pluripotent and self-renewing cells derived from the inner cell mass of preimplantation blastocysts
To study the role of Wnt signaling during neural differentiation, we used 46C mouse embryonic stem (ES) cells (EGFP was substituted into the ORF of the Sox1 gene) with the monolayer neural differentiation method
We showed that the expression of various Wnt signaling components is dynamically changed during neuronal differentiation (Figure 1), but the biological meaning of these changes and regulation of the expression of these genes are largely unknown
Summary
Embryonic stem (ES) cells are pluripotent and self-renewing cells derived from the inner cell mass of preimplantation blastocysts. These cells can differentiate into the following three germ layers: the ectoderm, mesoderm, and endoderm. Due to these characteristics, ES cells are considered useful tools in both research and regenerative medicine. It is important to understand how stem cells maintain their selfrenewal capacity and differentiate into each specific lineage [1,2,3]. ES cells can be differentiated into neuronal cell lineage in vitro. It is difficult to manipulate a specific lineage as RA treatment has been shown to induce other cell lineages
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