**11. GSK3 and NPC migration and polarization**

Correct positioning of newly generated neurons is crucial during development and for healthy function of the adult brain. Neuronal migration is tightly regulated by extracellular cues, including Wnts and growth factors. Accordingly, there is emerging evidence that their common downstream target, GSK3, may be involved in this process, primarily via regulation of cytoskeleton-associated proteins. Migration requires cellular polarization and extension at the leading edge of the cell. This involves dynamic reorganization of microtubules by a variety of microtubule-binding proteins. Several of these are directly phosphorylated and regulated by GSK3, including Tau, CRMP2, MAP1B, MAP2C, CLASP2, pVHL and APC (for reviews, see [145, 146]). Phosphorylation of many of these substrates by GSK3 reduces their ability to bind microtubules, thus making them less stable. Interestingly, GSK3 activity is typically low at the leading edge of migrating cells or at the tips of growing neurites in neuronal polarization [147-149]. This would promote substrate binding and stabilization of microtubules, facilitating forward movement of the cell's leading edge or growing neurite. Similarly, local inhibition of GSK3 activity is essential for polarization of newly generated neurons and growth of the nascent axon [150, 151]. Meanwhile, global inhibition of GSK3 induces formation of multiple axons [150, 152]. Several upstream inhibitors of GSK3 have been implicated in this process, including Cdc42 [149], ILK [153], LKB1 [147] and Akt [150]. Apart from the latter, these signaling proteins are not established regulators of GSK3 activity, so the precise molecular mechanisms by which they inhibit GSK3 activity await clarification.

factor signaling. Indeed, the protein phosphatase PP2A is a known component of the β-catenin/ APC/Axin signaling complex [156] and PP2A is able to activate GSK3 by dephosphorylating its N-terminal serine residue [157]. If this is true, these signaling complexes could be seen to *activate* GSK3 activity (at least phosphorylation of a particular substrate e.g. β-catenin). It might be more accurate to say that GSK3 is *not* inhibited by these pathways, but rather GSK3 *antagonizes* them. Then upon ligand stimulation, this function of GSK3 is alleviated by disruption of the signaling complex, activating the pathway. It is important to catalogue the pathway-specific targets of GSK3 and their effects on cell fate and survival, since this knowl‐ edge could identify novel therapeutic targets for artificially controlling neurogenesis and

Regulation of Cell Fate in the Brain by GSK3 http://dx.doi.org/10.5772/55180 165

Neurosignalling Group, Garvan Institute of Medical Research, Darlinghurst, Sydney,

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promoting recovery in diseased or damaged brains.

**Author details**

Adam R. Cole

**References**

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Australia
