Schematic of proposed mechanisms of astrocyte dedifferentiation. In uninjured brains where EGFR activity is low, derepression of mTOR upon p53 loss has no effect. Upon injury, the progressive increase in levels of EGFR ligands first destabilizes the identity of p53 null astrocytes in young adults and, in later life, causes their full dedifferentiation. This occurs through synergistic activation of mTOR signaling, which is switched on by EGFR and derepressed by p53 loss and drives translation of neurodevelopmental transcription factors to restore stemness programs in astrocytes. Teal and purple arrows indicate transcriptional and translational regulation, respectively. See alsoFigure S6.
