Functions of GSK-3 Signaling in Development of the Nervous System

Abstract

Glycogen synthase kinase-3 (GSK-3) is central to multiple intracellular pathways including those activated by Wnt/β-catenin, Sonic Hedgehog, Notch, growth factor/RTK, and G protein-coupled receptor signals. All of these signals importantly contribute to neural development. Early attention on GSK-3 signaling in neural development centered on the regulation of neuronal polarity using in vitro paradigms. However, recent creation of appropriate genetic models has demonstrated the importance of GSK-3 to multiple aspects of neural development including neural progenitor self-renewal, neurogenesis, neuronal migration, neural differentiation, and synaptic development.

Keywords: GSK-3; neural progenitor; neuronal migration.

Figure 1

Neural progenitors in the developing brain. Radial glial progenitors (RG) arise early in development from neuroepithelial cells. They are located in the ventricular zone (VZ) and have long radial processes that extend form VZ to the pial surface. A RG divides symmetrically to self-renew and asymmetrically to generate a daughter RG and a post-mitotic neuron or an intermediate progenitor (IP). IPs localize in the subventricular zone (SVZ) and divide symmetrically to produce neurons. There is another type of progenitors (oRG) in the superficial layer of SVZ or in the intermediate zone (IZ). Like RGs, oRGs have glial processes and can self-renew as well as generate neurons. For more information on oRG, see a recent review by Kriegstein and colleagues (Lui et al., 2011). The role of GSK-3 in regulating radial progenitors is now established. Functions related to IPs and oRGs remain to be investigated.

Figure 2

Glycogen synthase kinase-3 is a key regulator of multiple signaling pathways in neural progenitors. (A) GSK-3 controls gene induction by regulating the levels of transcription factors in neural progenitors. β-catenin is degraded via GSK-3 phosphorylation-dependent ubiquitin-protease machinery in the resting state. However, inhibition of GSK-3 by Wnt allows β-catenin accumulation. GSK-3 is also critical in the control of c-Myc levels. c-Myc is phosphorylated at T58 and recruited by ubiquitin-protease for degradation. FGF inhibits GSK-3 via AKT-mediated phosphorylation at S9 (beta) or S21 (alpha) and leads to increase in c-Myc levels. Inhibition of GSK-3 increases Notch intracellular domain (NICD) and Gli proteins in neural progenitors. Thus, GSK-3 activity is critical in the control of transcription factors in multiple signal pathways, which eventually regulates neural progenitors during development. (B) A schematic model of the GSK-3 function in apical–basal polarity and neurogenesis. GSK-3 is required for polarity establishment and possibly for neurogenic division of progenitors. Polarity-associated molecules including β-catenin, atypical PKC, APC, and cadherin are localized in the apical membrane. When progenitors divide, daughter cells that inherit the polarity molecules are thought to become progenitors. Without the polarity protein, cells become neurons. However, in GSK-3-deleted neural progenitors, polarity molecules are distributed throughout the cell. Thus, wherever the cleavage plane is positioned, daughter cells have almost same composition of the molecules. This may be an important factor that leads constant self-renewal of progenitors in GSK-3-deleted brains.

Figure 3

Glycogen synthase kinase-3 in neuronal migration. (A) GSK-3 is required for neuronal migration. During early stages of development, DISC1 that is an important regulator of neuron migration binds to GSK-3, resulting in dissociation of GSK-3 from β-catenin. The increased β-catenin level directs progenitors to self-renew. However, the binding activity of DISC1 decreases at later stages of embryogenesis, which induces reduction in β-catenin level via GSK-3 phosphorylation. Progenitors then produce more neurons that subsequently migrate from the ventricular zone (Ishizuka et al., 2011). (B) Microtubules are stabilized at the leading edge of migrating neurons by GSK-3 inactivation. LKB1 inactivates GSK-3 by the phosphorylation at S9. APC is dissociated from GSK-3 and binds to microtubules at the leading edge of migrating neurons (Asada and Sanada, 2010), which stabilizes microtubules (glu-tubulin).