Contextual Stat3 signaling in proliferating and differentiation NSCs. (A) Proliferation and survival of NSCs. A context in which Stat3 regulates the proliferation and survival of NSCs appears to include the cell surface receptor notch and its associated signaling pathways resulting in the activation of mTOR and activated ERK within the cell. Both mediate phosphorylation of Stat3 at serine 727. (B)Glial differentiation. Stat3 is activated by phosphorylation on both serine 727 and tyrosine 705. Stat3 signal are activated in a context which includes the notch-mediated signals hes and NF1, retinoic acid signaling and inhibition of neurogenin (ngn). Epigenetic modifications include retinoic acid-mediated histone acetylation, and NFI-mediated demethylation. Other known signals include cytokine and growth factor-mediated activation of JAK and ERK kinases, and change in methylation status CpG on DNA, and on histone H3 to allow transcription. Notch activation may be achieved by release of notch ligands by neighboring neuronal precursors which confers a glial fate on recipient cells. (C) Neuronal differentiation. Signals from NeuroD and ngn are central to neuronal differentiation. This occurs in a context where activities of ERK, disabled (dab) and MeCP2 are high. In addition to induction of neuron-specific genes by NeuroD and ngn, there is active repression of glial-specific promoters in neurons and neuronal precursors. Notch/Stat3-mediated signals are largely silent in this context, in contrast to glial differentiation.