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GSK3β negatively regulates oligodendrocyte differentiation and myelination in vivo
1Institute of Biology and Biomedical Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
Abstract:
Glycogen synthase kinase 3β (GSK3β) is an essential integrating molecule for multiple proliferation and differentiation signals that regulate cell fate. Here, we have examined the effects of inhibiting GSK3β 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 GSK3β inhibitors (ARA-014418, lithium, indirubin, and L803-mt) increase OPs and OLs and promote myelination. Inhibition of GSK3β stimulates OP proliferation and is prosurvival and antiapoptotic. The effects of GSK3β inhibition in OPs is via the canonical Wnt signaling pathway by stimulating nuclear translocation of β-catenin. However, direct comparison of the effects of Wnt3a and GSK3β inhibition in optic nerves shows that they have opposing actions on OLs, whereby GSK3β inhibition strikingly increases OL differentiation, whereas Wnt3a inhibits OL differentiation. Notably, GSK3β inhibition overrides the negative effects of Wnt3a on OLs, indicating novel GSK3β signaling mechanisms that negatively regulate OL differentiation. We identify that two mechanisms of GSK3β 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 GSK3β inhibition has equivalent effects in the adult and stimulates the regeneration of OLs and remyelination following chemically induced demyelination. This study identifies GSK3β as a profound negative regulator of OL differentiation that contributes to inefficient regeneration of OLs and myelin repair in demyelination.
Insights
Inhibiting Glycogen synthase kinase 3 beta (GSK3β) promotes oligodendrocyte development and myelin repair. This discovery offers new therapeutic avenues for demyelinating diseases by enhancing oligodendrocyte regeneration.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Glycogen synthase kinase 3 beta (GSK3β) integrates signals regulating cell fate.
- Oligodendrocytes (OLs) are crucial for myelin formation in the central nervous system.
- Dysfunctional OLs and poor remyelination contribute to demyelinating diseases.
Purpose of the Study:
- To investigate the role of GSK3β inhibition in oligodendrocyte development and myelination.
- To explore the mechanisms by which GSK3β affects oligodendrocyte precursor (OP) proliferation, survival, and differentiation.
- To assess the potential of GSK3β inhibition for promoting remyelination in demyelinated tissues.
Main Methods:
- Inhibition of GSK3β in vivo (lateral ventricle injection in postnatal mice) and ex vivo (organotypic optic nerve cultures).
- Administration of various GSK3β inhibitors (e.g., ARA-014418, lithium).
- Analysis of OP and OL numbers, proliferation, apoptosis, differentiation, and myelination.
- Investigation of downstream signaling pathways including Wnt/β-catenin, CREB, and Notch1.
Main Results:
- GSK3β inhibition significantly increased OP and OL numbers and promoted myelination.
- Inhibition of GSK3β stimulated OP proliferation, survival, and differentiation.
- GSK3β inhibition activated the canonical Wnt pathway but counteracted Wnt3a's inhibitory effect on OL differentiation.
- Mechanistically, GSK3β inhibition stimulated CREB and decreased Notch1 signaling, both impacting OL differentiation and myelination.
- GSK3β inhibition promoted OL regeneration and remyelination in adult mice following demyelination.
Conclusions:
- GSK3β is a significant negative regulator of oligodendrocyte differentiation and myelin repair.
- Inhibiting GSK3β enhances oligodendrocyte development and stimulates remyelination.
- Targeting GSK3β represents a promising therapeutic strategy for treating demyelinating diseases.
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