Recent evidence suggests that glycogen synthase kinase 3s (GSK 3s) and their upstream and downstream regulators have key roles in many fundamental processes during neurodevelopment. Disruption of GSK3 signaling adversely affects brain development and is associated with several neurodevelopmental disorders. Here, we discuss the mechanisms by which GSK3 activity is regulated in the nervous system and provide an overview of the recent advances in understanding how GSK3 signaling controls neurogenesis, neuronal polarization, and axon growth during brain development. These studies suggest GSK3 as a major signaling node that mediate multiple signaling molecules regulating neurodevelopment, such as DISC1, Par3/6, and Wnts.
Glycogen synthase kinase 3s are serine/threonine kinases that were originally identified as key regulatory enzymes in glucose metabolism1, 2. There are two isoforms, GSK3α and GSK3β, encoded by separate genes, which are overall 85% homologous to each other, with 95% identity in the kinase domains3. In rodents and humans GSK3β2, an alternative splice variant of GSK3β has been reported, which contains a 13 amino acid insertion in an external loop near the catalytic domain4. In contrast to the ubiquitously expressed GSK3β1, GSK3β2 is expressed specifically in the nervous system, with the highest levels found during development4. Interestingly, recent studies suggest that GSK3β2 plays a specific part in neuronal morphogenesis in vitro5, 6, and it remains to be determined whether different isoforms have specific functions in vivo during brain development. Since their discovery, GSK3s have been shown to mediate various signaling pathways, among which the growth factor and Wnt signaling pathways are the most studied7. Consistent with the roles of growth factors and Wnt proteins in the nervous system, especially during neurodevelopment, emerging evidence points to GSK3s as key regulators in multiple neurodevelopmental processes, including neurogenesis, neuronal migration, neuronal polarization and axon growth and guidance.
How do GSK3s regulate such a wide spectrum of developmental events? The answer may lie in the broad range of GSK3 substrates. Among GSK3 substrates are many transcription factors, such as cAMP response element-binding protein (CREB)8, nuclear factor of activated T-cells (NFAT)9, 10, neurogenin 211, Smad112, c-Jun13, and β-catenin14, all of which play important parts in the regulation of gene expression throughout neurodevelopment. GSK3s regulate these transcription factors by controlling their protein levels, DNA binding activities, and/or nuclear localization. In addition to gene expression, cell morphogenesis requires reorganization of the cytoskeleton, especially microtubules. GSK3s regulate the activity of several microtubule-associated proteins (MAPs)15, and so might control mitotic spindle reorganization during cell division, coordinated movement of the leading process and soma during neuronal migration, and directed growth cone advancement during axon growth and guidance, all of which require coordinated control of microtubule dynamics. Changes in GSK3 activity have been associated with many psychiatric and neurodegenerative diseases, such as Alzheimer’s disease, schizophrenia, and autism spectrum disorders, and it has become increasingly apparent that GSK3 might be a common therapeutic target for different classes of psychiatric drugs16, 17. Indeed, lithium, a direct inhibitor of GSK318, has been used in humans as a mood stabilizer for over 50 years19. The hypothesis that disturbances of brain development play a part in the etiology of these disorders is further supported by the fact that several genetic susceptibility factors for psychiatric disorders have key roles in neurodevelopment. Intriguingly, many of the genes associated with schizophrenia encode proteins involved in GSK3 signaling, such as Disrupted-In-Schizophrenia 1 (DISC1), Neuregulin 1, and Frizzled-320. Genes associated with autism spectrum disorders also encode proteins that are involved in the modulation of or that are affected by GSK3 activity, including phosphatase and tensin homolog deleted on chromosome 10 (PTEN)21, DISC122, serotonin23, tuberous sclerosis complex 1/2 (TSC1/2)24, and adenomatous polyposis coli (APC)25, 26. Therefore, a better understanding of the role of GSK3 in neurodevelopment could provide insight into the etiology of these disorders and possibly open up the potential of a new library of therapeutic targets.
In this Review, we provide an overview of the involvement of GSK3 signaling in neurodevelopment, with a particular emphasis on neurogenesis, neuronal polarization, and axon growth. We will also discuss the potential crosstalk between GSK3 signaling and other pathways that are implicated in these developmental steps.