**2. GSK3 and neurogenesis**

In 1980, Hammond and Dale noticed that lithium treatment of grey collie dogs increased their blood cell counts, which they suggested was due to increased proliferation of haematopoetic stem cells [4]. This was confirmed shortly afterwards [5], although the mechanism for lithium's action was not understood. In 1996, GSK3 was identified as a key target of lithium in cells [6], although it was another 8 years before a key role for GSK3 in regulating stem cell pluripotency was elucidated [7, 8]. Pharmacological inhibition of GSK3 activity was shown to maintain the undifferentiated phenotype in mouse and human embryonic stem (ES) cells, while its with‐ drawal promoted differentiation into multiple cell lineages [7]. More recently, it was demon‐ strated that the complex mixture of cytokines, growth factors, hormones, serum and feeder cells traditionally used to maintain self-renewal of ES cells can be replaced with two pharma‐ cological inhibitors; a MAPK inhibitor and a GSK3 inhibitor [8], thus emphasizing the importance of GSK3 for regulating pluripotency. The GSK3 substrates c-myc [9] and Klf5 [10] are among several transcription factors that have been used to induce pluripotency (iPS system). Thus, GSK3 is a key regulator of neurogenesis, although the precise molecular mechanisms are not yet fully understood. This review provides an overview of the extracel‐ lular stimuli and intracellular signalling pathways controlling GSK3 activity, as well as the downstream targets of GSK3 directly linking it to cellular proliferation and differentiation in the brain. GSK3 inhibitors are currently in clinical trials for several neurological disorders associated with impaired neurogenesis, therefore it is timely that cell fate pathways involving GSK3 are delineated.
