**Acknowledgements**

**Figure 3. Modulation of neurogenesis and gliogenesis after adult brain injury by members of the TGF-β cyto‐ kine superfamily.** In the top panel, the dentate gyrus (DG) in the hippocampus and subventricular zone (SVZ) of the lateral ventricles are shown after damage to the cerebral cortex. Note the proliferation and migration of cells from the SVZ and DG towards the infarcted area (blue arrows). Red dots represent proliferating and migrating neural stem cells and progenitors cells (NSPCs) located in these neurogenic regions. In the bottom panel, the role of TGF-β proteins at different stages of neurogenesis or gliogenesis after adult brain injury is illustrated. Proliferation, migration or differ‐ entiation are induced or inhibited by growth factors, such as: TGF-β, BMPs proteins, Activin, Follistatin or Noggin. After injury to the brain, TGF-β1 can increase proliferation of NSPCs and induce the differentiation of neuroblasts into neu‐ rons within the SVZ, [119]. BMP7 can induce neural stem cell proliferation, neuronal migration and differentiation [145]; other BMPs proteins (BMP2-7) also can stimulate neuronal migration [94]. The BMP inhibitor proteins noggin and chordin promote NSPC migration and oligodendrocyte proliferation and differentiation, while decreasing astro‐ cyte proliferation [115, 169]. After injury to the brain, within the DG TGF-β1 can reduce the proliferation of immature neurons while increasing neuronal migration and differentiation [165, 166]. BMP7 can enhance NSPC proliferation and neuronal differentiation [96, 145]. Noggin can also increase NSPC proliferation [169]. Generally, BMPs can in‐ crease astroglial differentiation and inhibit oligodendrocyte generation, and the BMP inhibitors Chordin and Noggin can facilitate oligodendrocyte differentiation and proliferation [181]. Activin can induce NSPCs proliferation, and de‐ crease microglial and astroglial proliferation. The activin antagonist, follistatin, reduces proliferating NSPCs and mi‐ grating neuroblasts [88]. In summary, the proliferation, migration and differentiation of cells in the SVZ and the DG

20 Trends in Cell Signaling Pathways in Neuronal Fate Decision

may be influenced by the spatial and temporal expression profile of these TGF-β proteins after brain injury.

This study was supported by grant from the Center for Neuroscience and Regenerative Medicine (CNRM). SV is supported by a CNRM postdoctoral fellowship. The opinions and assertions contained herein are the private opinions of the authors and are not to be construed as reflecting the views of the Uniformed Services University of the Health Sciences or the US Department of Defense.

#### **Author details**

Sonia Villapol, Trevor T. Logan and Aviva J. Symes

Department of Pharmacology and Center for Neuroscience and Regenerative Medicine, Uni‐ formed Services University of the Health Sciences, Bethesda, MD, USA

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**Chapter 2**

**Insulin/IGF-Signalling in Embryonic and Adult Neural**

The IIS cascades are initiated by binding of Insulin or Insulin-like growth factors (IGF-1 and -2) to their receptors, the Insulin receptor (IR), and the two Insulin-like growth factor receptor 1 (IGF-1r) and 2 (IGF-2r) (Fig. 1). While high affinity binding occurs between the cognate ligand-receptor pairs, each ligand binds to the other receptors with lower affinity [2]. IR, IGF-1r and -2r are dimers that occur as homo- but also as heterodimers, the latter of which are studied in various cancer cells [3]. Such hybrid receptors are also found in the central nervous system, however a clear function for them has not emerged as yet [4] although activation of different signalling cascades followed by a different biological effect is a likely scenario [2]. IR, IGF-1r and -2r are tyrosine receptor kinases that phosphorylate themself as well as downstream adaptor proteins like the insulin receptor substrate proteins (IRS-1-4) [5]. Through phosphor‐ ylation, IRS proteins bind to SRC-homology-2 (SH-2) domain-containing proteins like SRC, SRC homology2-B (SH2-B), protein phosphatases like Tyrosine-protein phosphatase non-

receptor type 1 (PTPN1), or the p85 subunit of phosphatidyl inositol 3-kinase (PI3K).

Two major signalling pathways are activated through IIS: the PI3K- and/or the RAS/Mitogenactivated protein kinase- (MAPK) pathways that are implicated in the regulation of a plethora

PI3K belongs to a family of lipid kinases that are grouped into three classes. Class IA PI3K are heterodimers of a p110 catalytic and a p85 or p55 regulatory subunit [6]. Binding of PI3K is followed by activation of the p110 catalytic subunit of the kinase, which catalyses the increase

> © 2013 Vogel; 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,

© 2013 Vogel; 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.

distribution, and reproduction in any medium, provided the original work is properly cited.

**Proliferation and Differentiation in the Mammalian**

**Central Nervous System**

http://dx.doi.org/10.5772/54946

of different cellular processes.

Additional information is available at the end of the chapter

**1.1. General overview of insulin/IGF-signalling**

Tanja Vogel

**1. Introduction**

