科研之友
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摘要
Glycogen synthase kinase 3 beta (GSK3 beta) is an essential integrating molecule for multiple proliferation and differentiation signals that regulate cell fate. Here, we have examined the effects of inhibiting GSK3 beta on the development of oligodendrocytes (OLs) from their oligodendrocyte precursors (OP) in vivo by injection into the lateral ventricle of postnatal mice and ex vivo in organotypic cultures of isolated intact rodent optic nerve. Our results show that a range of GSK3 beta inhibitors (ARA-014418, lithium, indirubin, and L803-mt) increase OPs and OLs and promote myelination. Inhibition of GSK3 beta stimulates OP proliferation and is prosurvival and antiapoptotic. The effects of GSK3 beta inhibition in OPs is via the canonical Wnt signaling pathway by stimulating nuclear translocation of beta-catenin. However, direct comparison of the effects of Wnt3a and GSK3 beta inhibition in optic nerves shows that they have opposing actions on OLs, whereby GSK3 beta inhibition strikingly increases OL differentiation, whereas Wnt3a inhibits OL differentiation. Notably, GSK3 beta inhibition overrides the negative effects of Wnt3a on OLs, indicating novel GSK3 beta signaling mechanisms that negatively regulate OL differentiation. We identify that two mechanisms of GSK3 beta inhibition are to stimulate cAMP response element binding (CREB) and decrease Notch1 signaling, which positively and negatively regulate OL differentiation and myelination, respectively. A key finding is that GSK3 beta inhibition has equivalent effects in the adult and stimulates the regeneration of OLs and remyelination following chemically induced demyelination. This study identifies GSK3 beta as a profound negative regulator of OL differentiation that contributes to inefficient regeneration of OLs and myelin repair in demyelination.
- 出版日期2011-4
