**1. Introduction**

The human brain is the most complex object in the known universe. It contains ~100 billion neurons, each forming between 1,000 and 10,000 connections with other neurons to form interconnecting circuits containing up to 1,000 trillion connections. This extreme complexity arises from a single cell at conception. Therefore, brain development needs to be tightly controlled to ensure proper patterning and circuit formation. Defects in this process lead to debilitating neurodevelopmental disorders, including autism and microcephaly. Until recently, it was assumed that once an adult brain had matured, it was 'fixed' or 'hard-wired' and no new neurons were generated. However, research over the last 15-20 years has dem‐ onstrated the existence of neural precursor cells (NPC's) that produce and incorporate new neurons into existing circuits of the adult brain, a process known as neurogenesis [1]. Adult neurogenesis is similar in organisation and mechanism to early brain development [2]. The ability to control neurogenesis could enable the brain to repair itself following injury (e.g. stroke, spinal chord injury, head trauma) and to enhance mental functioning (e.g. delay or prevent age-related cognitive decline and neurodegenerative diseases). Therefore, there is a clear and urgent need to understand the mechanisms controlling neurogenesis in the devel‐ oping and adult brain.

NPC's give rise to all cell types in the brain by undergoing asymmetric cell division, generating one daughter cell that retains pluripotency and another daughter cell that is committed to a neuronal or glial fate. In adults, this predominantly occurs in the dentate gyrus of the hippo‐ campus and the subventricular zone/olfactory system. Thousands of new cells are generated every day in the hippocampus, although less than half survive beyond a few weeks to permanently integrate into adult brain circuits [3]. This process is an important component of neuroplasticity in the hippocampus, facilitating learning and memory. Other brain regions are thought to have limited neurogenic potential that might be induced following injury. The fate of NPC's is controlled by extracellular stimuli (e.g. growth factors, Wnt, Notch, Hedgehog)

© 2013 Cole; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Cole; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

that trigger intracellular signalling pathways and changes in gene transcription, although the transcriptional regulators targeted by these signalling pathways and their target genes are yet to be fully clarified.

(Ser21 in GSK3α, Ser9 in GSK3β) [15, 16]. This phosphoserine acts as a pseudo-substrate and binds to the phosphate-binding pocket on GSK3, preventing interaction with primed sub‐ strates [17]. Phosphorylation is mediated by members of the AGC family of kinases (e.g. Akt) and commonly occurs downstream of growth factor and PI3K signaling [15]. Activation of the canonical Wnt signaling pathway also inhibits GSK3 activity, preventing phosphorylation of β-catenin, although this is not mediated by N-terminal phosphorylation, but by proteinprotein interactions [18, 19]. GSK3 is also modified by phosphorylation at a tyrosine residue on the activation loop of the kinase domain (Tyr279 for GSK3α and Tyr216 for GSK3β). Phosphorylation at these sites is absolutely required for kinase activity and is most likely

Regulation of Cell Fate in the Brain by GSK3 http://dx.doi.org/10.5772/55180 155

Valuable information on the role of GSK3 in cell fate determination has been obtained from mice genetically modified to either increase or decrease expression of GSK3α and β. While GSK3β-knockout mice die in late development due to defects in heart development and/or hepatic apoptosis [22, 23], GSK3β-heterozygous mice and GSK3α-knockout (homozygous) mice are viable and display several behavioural defects, including increased anxiety, decreased aggression and memory defects [24-28]. Also, GSK3α-null mice exhibit decreased numbers and size of Purkinje cells in the cerebellum [24]. Conditional overexpression of GSK3β in the forebrain using the doxycycline/Tet system impaired memory and spatial learning in mice [29]. At the cellular level, GSK3β overexpression increased neuronal cell death, astrocytosis, gliosis and reduced LTP induction. These effects could be restored by reducing GSK3 activity to normal levels by silencing the transgene or by treatment with lithium [30, 31]. In another report, overexpression of GSK3β-S9A in post-natal neurons (Thy-1 promoter) reduced brain size in adult mice, especially in the cerebral cortex, predominantly caused by reduced size of neuronal cell bodies and the somatodendritic compartment [32]. Together, these observations clearly demonstrate that GSK3 is important for healthy development and function of the brain.

In addition to conventional under/over-expression mouse models, GSK3-knockin mice were developed that are insensitive to growth factor inhibition (Ser21/9 mutated to Ala in GSK3α and β, respectively), but remain sensitive to Wnt-induced inhibition [33]. These mice are viable and display no overt developmental or growth defects, but do exhibit increased susceptibility to hyperactivity, stress-induced depression and mild anxiety, as well as abnormal LTP and memory functions [34, 35]. NPC's isolated from GSK3-knockin mice exhibit reduced neuro‐ genesis, despite normal proliferation [36], suggesting defective differentiation/maturation or survival of NPC's. In contrast, mice with double homozygous deletion of GSK3α and β isoforms (i.e. all GSK3 isoforms deleted) display a dramatic increase in proliferation of NPC's and decreased differentiation into post-mitotic neurons [37]. This is accompanied by deregu‐ lation of Wnt, Notch, Hedgehog and FGF signalling pathways. In another mouse model, mice expressing a mutant form of the scaffolding protein Disrupted in Schizophrenia (DISC1), which is mutated in schizophrenia and mood disorder patients, display increased GSK3 activity, causing inhibition of the Wnt signaling pathway and decreased NPC proliferation

constitutively modified (i.e. not regulatable) [20, 21].

**4. Neurogenesis in GSK3 mutant mice**
