Götz, Berninger

Project Title: Role of Sox2 in the direct lineage reprogramming of astroglia and pericytes into neurons

Reprogramming of somatic cells into neurons provides a new approach towards cell-based therapy of neurodegenerative diseases_ENREF_1. We could recently show that cells from the adult human cerebral cortex expressing pericyte markers, such as PDGF receptor-b, can be reprogrammed in vitro into bIII tubulin- and MAP2-positive neurons by co-expression of the basic helix-loop-helix transcription factor Mash1 (mammalian homologue of achaete-schute-1) and the SRY-related HMG box protein Sox2, but not by either factor alone. Importantly, the synergistic effect of Sox2 on neuronal reprogramming induced by proneural genes is not restricted to pericytes, but can also be observed in astrocytes. Postnatal astrocytes become refractory to neuronal reprogramming by Neurog2 upon maturation in vitro, but forced co-expression of Sox2 maintains (or renders) these cells reprogrammable by either Neurog2 or Mash1. Consistent with a more widespread reprogramming capacity of Sox2 and proneural genes we could also show that co-expression of Sox2 and Mash1, but neither factor alone, could elicit neurogenesis from proliferative cells in the injured cerebral cortex in vivo. In the present proposal we aim at unraveling the molecular mechanisms underlying the Sox2-mediated enhancement of astroglia- or pericyte-to-neuron lineage conversion by analyzing changes in the astrocyte or pericyte transcriptome in response to Sox2.