Regenerative potential of targeting glycogen synthase kinase-3 signaling in neural tissues

Multiple roles of glycogen synthase kinase-3 (GSK-3) in neural tissues: GSK-3 is a serine/threonine kinase that has two isoforms encoded by two different genes, GSK-3α and GSK-3β, in mammals. GSK-3 has several sites of serine and tyrosine phosphorylation. Its activity is negatively regulated by phosphorylation of serine 21 for GSK-3α and serine 9 for GSK-3β, while it is positively regulated by phosphorylation of tyrosine 279 for GSK-3α and tyrosine 216 for GSK-3β. GSK-3 was initially found to be an important component of glycogen metabolism. However, recent studies have revealed that GSK-3 is a multifunctional kinase in various cell types, including neural cells. GSK-3α and GSK-3β are highly expressed in neural tissues such as the cerebral cortex, the hippocampus, the cerebellum, and the spinal cord. In particular, GSK-3β is elevated in the aged hippocampus, and more abundant than GSK-3α in rodents (Salcedo- Tello et al., 2011). Also, GSK-3β is highly expressed in neurons and astrocytes in the developing brain and spinal cord. In neurons, GSK-3 directly leads to the phosphorylation of several neuronal microtubule- associated proteins (MAPs), especially microtubule plusend tracking proteins (+TIP), including collapsin response mediator protein-2 (CRMP-2), adenomatous polyposis coli (APC), cytoplasmic linker associated protein (CLASP), MAP1B, MAP2, microtubule actin cross-linking factor 1 (MACF1), and Tau (Kim and Snider, 2011). GSK-3 phosphorylation of primed-MAPs generally decreases their activity and thus leads to a decrease in microtubule stability in neurons. Localized inhibition of GSK-3 activity at the axon terminal is required for axon growth during development and regeneration after injury (Alabed et al., 2010). Meanwhile, phosphorylation by GSK-3 activates some unprimed-substrates such as MAP1B, which stabilizes microtubules for axon extension. This is why global inhibition of GSK-3 at a high degree using pharmacological inhibitors or genetic elimination of both isoforms suppresses axon growth (Kim et al., 2006). GSK-3 is also a master regulator of neural stem cell proliferation and differentiation. Loss of both GSK-3 alleles leads to an increase in neural stem cell and progenitor proliferation (Kim et al., 2009). Similarly, pharmacological inhibition of GSK-3 by SB-216763 maintains pluripotency in neural stem cells. Additionally, GSK-3 plays an important role in astrocyte and oligodendrocyte development. The rate of astrocyte apoptosis is increased by overexpression of a constitutively-active GSK-3β mutant in primary cortical astrocytes. Both the number and size of astrocytes are significantly increased in GSK-3 mutant mice when both GSK-3 isoforms are genetically eliminated in astrocyte progenitors and mature astrocytes using a GFAP-cre driver (Jung et al., 2015). Also, pharmacological inhibition of GSK-3 with lithium and indirubin results in increased numbers of oligodendrocyte progenitors and mature oligodendrocytes. Finally, elevated GSK-3 activity is correlated with neuronal death. For example, overexpression of GSK-3β significantly increases neuronal cell death, and pharmacological inhibition of GSK-3 promotes the survival of several types of neural cells. Therefore, GSK- 3 is a major factor in many facets of neural cell regulation, such as neurogenesis, neural stem cell proliferation, neural cell death, neuronal differentiation, and gliogenesis (Kim and Snider, 2011).