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GSK3 signalling in neural development

Key Points

  • Recent studies provide strong evidence that glycogen synthase kinase 3 (GSK3) signalling has important roles in many neurodevelopmental processes, such as neurogenesis, neuronal polarization and axon outgrowth.

  • Results from GSK3α-Ser21Ala/GSK3β-Ser9Ala double knock-in mice suggest that phosphorylation of GSK3s at their amino-terminal serine residues is not the major regulatory mechanism to control GSK3 activity in the nervous system. Other factors — such as disrupted in schizophrenia 1 (DISC1), partitionary defective 3 (PAR3) and low-density lipoprotein receptor-related protein 6 (LRP6) — may have more important roles in the regulation of GSK3 activity.

  • Evidence suggests that during neurogenesis, GSK3 inactivation promotes neural progenitor proliferation, whereas GSK3 activation promotes neuronal differentiation. The role of GSK3 in neurogenesis might be achieved through regulation of protein stability and microtubule assembly.

  • Several lines of evidence suggest that GSK3 signalling controls neuronal polarization by regulating microtubule stability through several microtubule-binding proteins. GSK3 signalling seems to be the converging point of many pathways that regulate neuronal polarity, such as the phosphatidylinositol 3-kinase (PI3K)–Akt pathway, the PAR3–PAR6–atypical protein kinase C (aPKC) pathway, the LKB1–SAD pathway, and the tuberous sclerosis (TSC) complex–mammalian target of rapamycin (mTOR) pathway.

  • GSK3 as pleiotropic roles in controlling axon outgrowth depending on the substrates involved. Local inactivation of GSK3 towards primed substrates at distal axons is necessary for efficient axon outgrowth, whereas strong suppression of GSK3 activity prevents axon outgrowth, probably through regulation of unprimed substrates. GSK3 signalling can also regulate axon outgrowth by controlling transcriptional factors in the cell soma.

  • The important role of GSK3 signalling in neural development is consistent with its involvement in neurodevelopmental disorders, such as schizophrenia and autism. Further studies may point to novel therapeutic treatments that target GSK3 signalling.

Abstract

Recent evidence suggests that glycogen synthase kinase 3 (GSK3) proteins and their upstream and downstream regulators have key roles in many fundamental processes during neurodevelopment. Disruption of GSK3 signalling 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 the understanding of how GSK3 signalling controls neurogenesis, neuronal polarization and axon growth during brain development. These recent advances suggest that GSK3 is a crucial node that mediates various cellular processes that are controlled by multiple signalling molecules — for example, disrupted in schizophrenia 1 (DISC1), partitioning defective homologue 3 (PAR3), PAR6 and Wnt proteins — that regulate neurodevelopment.

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Figure 1: Proposed models of GSK3 inactivation.
Figure 2: Neural development of the mammalian neocortex.
Figure 3: Proposed model for the role of GSK3 signalling during neurogenesis.
Figure 4: GSK3 in the regulation of neuronal polarization.
Figure 5: Differential regulation of GSK3 substrates during axon growth.
Figure 6: Potential roles of GSK3 in the transcriptional regulation of axon growth.
Figure 7: Representative substrates of GSK3 that are implicated in neural development.

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Acknowledgements

The authors were supported by the Whitehall Foundation (to F.Q.Z), the Basil O'Connor Starter Scholar Research Award from the March of Dimes foundation (to F.Q.Z) and the US National Institutes of Health grant 1R01NS064288. We apologize to authors whose work we were unable to include owing to space constraints.

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Glossary

Mitotic spindle reorganization

Reorganization of microtubules and associated molecules during cell division to form a bipolar spindle between duplicated centrosome components. This leads to the segregation of chromosomes.

Leading process

A neuronal process that extends in the direction of neuronal migration before nuclear movement.

Leading edge

The region of a migrating cell that protrudes forward.

Asymmetrical division

Division of cells that leads to the production of two daughter cells with different developmental potentials.

Centrosome

An organelle that controls the organization of microtubules and regulates cell-cycle progression.

Centriole

One of two perpendicular structures in the centrosome that are composed of a ring of nine microtubules.

Ventricular zone

A region in the brain next to the ventricles that is composed of neuroepithelial cells that generate neuronal and glial cells.

Microtubule minus end-anchoring proteins

A family of proteins that specifically bind to the microtubule minus ends and function to anchor the microtubule to specific cellular structures, such as the centriole.

Microtubule plus end-binding proteins

A family of microtubule-binding proteins that specifically track the growing ends (plus ends) of microtubules and function to stabilize microtubules or to mediate the interactions between microtubules and other cellular structures.

Microtubule plus end

The more quickly polymerizing end of microtubule polymers.

Kinetochore

A specialized condensed region on the chromosome to which the spindle fibres attach during cell division.

Cell cortex

A cytoplasmic region beneath the plasma membrane that functions as a mechanical support of the plasma membrane.

Myristoylation

An irreversible protein modification that covalently attaches a myristoyl group, using an amide bond, to the α-amino group of an amino-terminal amino acid of a nascent polypeptide.

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Hur, EM., Zhou, FQ. GSK3 signalling in neural development. Nat Rev Neurosci 11, 539–551 (2010). https://doi.org/10.1038/nrn2870

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