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Chapter

2 Extrinsic and Intrinsic Factors Modulating Proliferation and Self-renewal of Multipotential CNS Progenitors and Adult Neural Stem Cells of the Subventricular Zone Sara Gil-Perotin1,2 and Patrizia Casaccia-Bonnefil1 Introduction Regulationofcellnumberingerminalzonesofthenervoussystemisdependent on the interaction of extracellular signals with the '

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intrinsic'

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properties of the germinal cells that may vary depending on the developing stage of the organ- ism.

During early embryonic development, proliferation of cells occurs along the lumen of the developing neural tube, in an area defined as '

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the ventricular zone'

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. At this stage, cells proliferate very fast and characteristically give rise to identical daughter cells, via a process identified as '

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symmetric cell division'

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that allows for expansion of the primordial structures (Fig. 2.1A). As the organism develops, the need for '

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rapid expansion'

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decreases and new struc- tures begin to form while still allowing for growth of the organism. Therefore, bymid-gestation,asecondgerminalzonearises,thesubventricularzone(SVZ) and cells in this area acquire a modality of cell division characterized by the generation of two different daughter cells ('

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asymmetric cell division'

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): One with the ability to self-renew and the other one with the ability to differentiate into a specific lineage (Temple, 2001). In adult SVZ, the maintenance of homeostasis induces stem cells and multipotential progenitors to divide asym- metrically, unless a need for rapid expansion (e.g. repair after injury) induces the cells to shift to a symmetric modality of division (Fig. 2.1B). Changes in the levels of the extracellular signals, alterations of their receptors or modification of the intracellular signaling molecules regulating proliferation during embryonic development, may result in abnormalities of

1 Department of Neuroscience and Cell Biology, UMDNJ R. Wood Johnson Medical School,

675 Hoes Lane, Piscataway, NJ 08854, USA

2 Department of Comparative Neurobiology, Instituto Cavanilles de Biodiversidad y Biologia evolutiva,

46980 Paterna, Valencia, Spain Levison / Mammalian Subventricular Zones chap02 Final Proof page

30 15.10.2005 12:48pm

30 Figure 2.1. Schematic representation of the distinct modalities of cell division. During development (A), the expansion of brain structures is first guaranteed by the rapid and symmetric non-terminal cell division. As new cell types are generated, the pattern of cell division becomes asymmetric. In the adult animal (B) it is likely that stem cells (B cells) in the remaining germinal zones such as the SVZ undergo asymmetric cell division to maintain a specific number of mother and daughter cells. '

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Multipotent progenitors (C cells) undergo a similar pattern of asymmetric cell division and generate A cells and oligodendrocyte progenitors (not shown), with the ability to divide following a symmetric division where both daughter cells exit from the cell cycle (Q) and differentiate. Note that upon injury, the need for expansion of the progenitor population leads to symmetric division and expansion of C cells that generate both neurons and oligodendrocytes.'

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Levison / Mammalian Subventricular Zones chap02 Final Proof page

31 15.10.2005 12:48pm 2. Extrinsic and Intrinsic Factors Modulating Proliferation

31 brain structures. Changes or modifications of extracellular or intracellular signals in adult neural stem cells, in contrast, may not affect the histoarch- itecture of the brain, but affect the number of multipotential progenitors available for repair after injury. If proliferation is defective, a smaller num- ber of cells will be available for repair, conversely, if proliferation proceeds uncontrolled, larger number of cells may result in hyperplastic foci and eventually lead to neoplastic transformation. Since the responsiveness of neural stem cells and multipotential progenitors to extracellular signals is a dynamic process dependent on the developmental stage and on the regional localization of the cells, it becomes important to recognize that conclusions based on studies on embryonic stem cells may not be translated directly to adult neural stem cells. These temporally and devel- opmentally restricted profiles of responsiveness to mitogenic and anti-mito- genic signals are determined by several parameters, including the bioavailability of extracellular signals, the presence of specific receptors, cross-talks among distinct signaling pathways and modulation of cell cycle regulatory molecules. All of these events can be affected or determined by specific genetic traits, expression of transcription factors and epigenetic modi- fications of chromatin components resulting in differences of gene expression that modulate the '