Glial cells make neurons: molecular mechanisms of neurogenesis

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Neural stem cells of the adult mammalian CNS which can differentiate both into nerve or glial cells of the central and peripheral nervous system and into cells of other organs of the body, were recently identified as astrocytes, one of the two main types of glial cells. The frequency of astrocytes in the CNS is much higher when compared to nerve cells, but their stem cell characteristics are restricted to two small regions of the brain. The aim of this work will be the identification of factors which are crucial for their stem cell characteristics and differentiation into neurons. An important factor to direct astrocytes of non-neurogenic regions to a neuronal fate is the transcription factor Pax6. Analysis of function in our (Goetz) in vitro experiments showed that Pax6 is crucial for the neurogenic potential of radial glial cells and is able to stimulate astrocytes to differentiate into neurons. We now want to transfer these findings to the in vivo situation and examine Pax6 in different CNS lesion paradigms. Moreover, we aim to identity cell surface molecules mediating the neurogenic fate of glial cells initiated by Pax6. Interestingly, the cell adhesion molecules L1 and F3 (Schachner) were identified as targets of Pax6. Their role in astrocytes (both in stem cells and in astrocytes of non-neurogenic regions of the adult CNS) will be investigated in loss of function/increase of function analyses. On the one hand, we will investigate the neurogenic potential of the astrocytic stem cells of the adult SVZ and the hippocampus in F3 -/- and L1 -/- mice; on the other hand we want to misexpress L1 and F3 in astrocytes of non-neurogenic regions to see if there is a change in their proliferative or neurogenic capacity. The aim is to identify potential extrinsic stimuli that allow directing the ubiquitous astrocytes of the adult brain towards neuronal replacement in vivo. To identify additional cell surface molecules implicated in neurogenesis, we will use RNA profiling of neurogenic and non-neurogenic glial cells to identify possible targets for the regulation of the neurogenic potential with regard to therapeutic treatments.