Inflammatory mediators, many of which activate the signaling of nuclear factor kappa B (NF¿B), have received increasing attention in the field of neurogenesis. NF¿B signaling regulates neurite outgrowth and neural plasticity as well as the proliferation/apoptosis and terminal differentiation of neural stem cells (NSCs). Early neurogenesis from NSCs produces identical progeny through symmetric division and committed daughter cells through asymmetric division. Here, we show that NF¿B signaling is required for NSC initial differentiation. The canonical IKKß/I¿Ba/p65 pathway is activated during the initial stages of neural differentiation induced by treatment with TNFa or withdrawal of epidermal growth factor/basic fibroblast growth factor. NSC-specific inhibition of NF¿B in transgenic mice causes an accumulation of Nestin+/Sox2+/glial fibrillary acidic protein+ NSCs. Inhibition of NF¿B signaling in vitro blocks differentiation and asymmetric division and maintains NSCs in an undifferentiated state. The induction of initial differentiation and asymmetry by NF¿B signaling occurs through the inhibition of C/EBPß expression. Our data reveal a novel function of NF¿B signaling in early neurogenesis and provide insight into the molecular mechanisms underlying neurodevelopmental disorders and neurodegenerative diseases. STEM CELLS 2012;30:510–524

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