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Heins, Nico (2005): Intrinsic fate determinants of neural and multipotent CNS precursor cells. Dissertation, LMU München: Faculty of Biology
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Abstract

The cells of the mammalian central nervous system (CNS) arise from multipotential precursor cells. The mechanisms that drive precursor cells toward a distinct cell fate are not well understood. Since transcription factors are known to control fate decisions, I attempted to determine the role of transcription factors Emx1, Emx2 and Pax6 that are particularly interesting since they specify area identities in the mouse telencephalon. To analyze their roles in precursor cells I chose gain-of-function experiments. Overexpression of these transcription factors showed that Emx2, Emx1 and Pax6 affect precursor cells in a region-specific manner. Emx2 transduction increases proliferation by promoting symmetric cell divisions, whereas blockade of endogenous Emx2 by antisense Emx2 mRNA limits the number and fate of progenitors generated by an individual cortical precursor cell. In the Emx2-/- asymmetrical cell divisions are increased in the cerebral cortex in vivo. In contrast to Emx2 Pax6 decreases proliferation. Pax6 deficient cells show more symmetrical cell divisions while Pax6 promotes asymmetric cell divisions in vitro. Emx2 endows in vitro cortical precursor cells with the capacity to generate multiple cell types, including neurons, astrocytes and oligodendrocytes. Emx1 keeps cells in an undifferentiated cell type, while Pax6 increases the proportion of neurons and can also convert astrocytes to neurons. The bHLH transcription factors Olig2 and Mash1 are up-regulated upon Emx2-transduction whereas Pax6 negatively influences those transcription factors and specifically up-regulates Ngn2. Thus, Emx2 is the first cell-intrinsic determinant able to instruct CNS precursors towards a multipotential fate. These results demonstrated an important role of Pax6 as intrinsic fate determinant of the neurogenic potential of glial cells. Taken together, Emx2 and Pax6 have opposing roles in cell proliferation, mode of cell division and cell fate.