**Author details**

Adam R. Cole

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

164 Trends in Cell Signaling Pathways in Neuronal Fate Decision

mechanisms by which they inhibit GSK3 activity await clarification.

**12. Conclusions**

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

It is clear that GSK3 is an important target of several signaling pathways controlling cell fate in the brain. It is also clear that many of these pathways can be activated simultaneously in the same cells/tissues. One possibility is that GSK3 acts as an integrator of these simultaneous inputs to determine the cellular outcome. That is, GSK3 acts as a node for multiple signaling pathways and the sum of these inhibitory signals dictates cell fate. This is unlikely, since although each of these pathways target GSK3, their downstream targets are different. For example, growth factor signaling inhibits phosphorylation of CRMP2, but not β-catenin, and *vice versa* for Wnt [19, 154, 155]. An alternative explanation is that different subsets of GSK3 substrates are selectively affected by particular stimuli. That is, ligand-stimulated activation of the Wnt, Notch and Hedgehog pathways prevents phosphorylation of a single substrate (βcatenin, Notch and Gli, respectively) by disrupting multi-subunit signaling complexes required to mediate their phosphorylation. This increases the stability of these proteins, translocation to the cell nucleus and regulation of gene transcription programs that promote proliferation of ES cells/NPC's. In contrast, growth factor-mediated inhibition of GSK3 via phosphorylation of N-terminal serine residues reduces phosphorylation of many substrates (although not β-catenin), promoting survival and differentiation of newly generated neurons. It is possible that signaling complexes associated with β-catenin (and perhaps Notch and Gli) are able to surmount the inhibitory N-terminal serine phosphorylation induced by growth Neurosignalling Group, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia
