**12. Conclusions**

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 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 promoting recovery in diseased or damaged brains.
