Molecular Fate Determinants in Embryonic and Adult Neural Stem Cells

7 2 ABSTRACT The molecular signals specifying neuronal, glial or multipotent precursors in the developing and adult central nervous system (CNS) are largely unknown. Radial glial cells have recently been discovered as major precursor population generating neurons or glial cells in separate lineages in the developing CNS. Towards this aim to identify the key molecular determinants for neurogenic versus gliogenic fate in radial glial cells I used a novel method to selectively enrich neurogenic or non-neurogenic radial glia and compared their gene expression to adult subependymal zone (SEZ) precursors in vitro and in vivo. The expression profile of the transcription factors Olig2 and Pax6 were particularly intriguing. Olig2 was 67 fold higher in multipotent compared to neuronal or glial precursors, while Pax6 showed strongest expression in neuronal precursors. I therefore focused further on the functional analysis of Pax6 and Olig2 in neural stem cell in vitro and in vivo. Interference with Olig2 in neural stem cells in vitro revealed its role in self-renewal. In adult neural stem cells of the SEZ overexpression of Olig2 promoted oligodendrocyte formation. Pax6, in contrast, proved to be a very potent neurogenic determinant since neurogenesis is not only Pax6-dependent in neural stem cells in vitro, but also in adult neural stem cell in vivo. Taken together, these results demonstrate a pathway combining transcription factors of dorsal and ventral regions that is activated in a specific lineage progression of adult neural stem cells in vitro and in vivo. Most importantly also in regard to therapeutic approaches, this work revealed the molecular mechanisms to direct adult neural stem cells towards a specific cell fate, neuronal or oligodendroglial. Zellschicksalsbestimmung neuraler Stammzellen aufzeigen. A central question in neural development is how different precursor populations differ on a molecular level. The adult central nervous system is composed of different neuronal and glial cell types that are generated during development. Different lines of evidence show a hierarchical fate restriction as depicted in Fig. 1. In most CNS regions multipotent precursors are sequentially more and more restricted during development to generate a specific cell type (Fig. 1). Early neuroepithelial precursors throughout the CNS are multipotent and can generate undifferentiated precursors, astrocytes, oligodendrocytes and neurons (McCarthy et al., 2000). However, during development, they do not generate these diverse cell types directly, but rather via precursors that are more restricted in their potential, i.e. generate exclusively a single cell type. This restriction occurs around …