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SOX2 functions in adult neural stem cells

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Sox2 is expressed highly in the neuroepithelium of the developing CNS and has been shown to function in neural stem cells. Because Sox2-null mutant mice fail to develop beyond implantation, the role of SOX2 in the CNS has lacked validation. A new genetic model addresses the role of SOX2 in the adult brain and provides evidence that it is involved in the maintenance of neurons in specific regions, in the proliferation and/or maintenance of neural stem cells, and in neurogenesis.

Introduction

The recent explosion of interest in stem cell research and its important clinical implications have brought into focus transcription factors of the SRY-related HMG box (SOX) family [1]. Sox2-null mutant embryos cannot give rise to embryonic or trophectoderm lineages, indicating that Sox2 plays an essential role in early embryo precursor cells and their in vitro stem cell equivalents [2]. Sox2 is expressed in other stem cells and precursor cells during development, including neural stem cells (NSC), and therefore it is likely to be involved in self-renewal and precursor differentiation. In the developing CNS, several studies have shown that all three closely related SoxB1 subfamily members, Sox1, Sox2 and Sox3, which are coexpressed in the neuroepithelium [3], function to maintain broad developmental potential and NSC identity 2, 4, 5, 6, 7. Sox1-null [8] and Sox3-null [9] mutant mice are viable and without general CNS defects, suggesting functional redundancy within the subfamily. These facts have prevented elucidation of the role of SOXB1 factors in NSC. However, a recent study by Ferri et al. [10] has established that Sox2 is expressed in adult NSC, and provides genetic evidence that it is involved in their maintenance and/or proliferation.

Section snippets

SOX2 functions in the adult brain

Neurogenesis continues in the adult brain in two germinal layers: the subventricular zone (SVZ) of the lateral ventricle, which provides neuronal precursors that migrate to the olfactory bulb via the rostral migratory stream throughout adult life, and the dentate gyrus subgranular zone of the hippocampus. Cells with structural and molecular characteristics of astrocytes (e.g. expressing glial fibrillary acidic protein, GFAP) are believed to function as neurogenic stem cells in these regions [11]

Molecular mechanism of SOXB1 function in neurogenesis

Proneural transcription factors drive neurogenesis by directing the exit of neural progenitors from the cell cycle and by mediating the expression of genes characteristic of post-mitotic neurons [15]. Bylund et al. [5] and Graham et al. [6] showed that inhibition of SOX2 using dominant-negative constructs promotes premature differentiation of precursors (i.e. exit from cell cycle, loss of progenitor markers and acquisition of early neuronal markers). They also proposed that SOXB1 factors can

Concluding remarks

Before we can really begin to understand the transcriptional networks operating in stem cell maintenance, proliferation and fate commitment, many experiments will be required to identify the specific cofactors, target genes and regulatory pathways of SOXB1 factors. However, the results discussed here highlight the importance of SOX2 in neural development and homeostasis of the adult CNS. Because SOX2 is expressed in other stem cells and developing systems during embryogenesis, more functions

Acknowledgements

I thank Robin Lovell-Badge (NIMR, London) for his advice in the preparation of this review. My laboratory is supported by the Medical Research Council.

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