Nuclear Factor Kappa B Signaling Initiates Early Differentiation of Neural Stem Cells

Inflammatory mediators, many of which activate the signaling of nuclear factor kappa B (NF kappa B), have received increasing attention in the field of neurogenesis. NF kappa 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 kappa B signaling is required for NSC initial differentiation. The canonical IKK beta/I kappa B alpha/p65 pathway is activated during the initial stages of neural differentiation induced by treatment with TNF alpha or withdrawal of epidermal growth factor/basic fibroblast growth factor. NSC-specific inhibition of NF kappa B in transgenic mice causes an accumulation of Nestin(+)/Sox2(+)/glial fibrillary acidic protein(+) NSCs. Inhibition of NF kappa 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 kappa B signaling occurs through the inhibition of C/EBP beta expression. Our data reveal a novel function of NF kappa B signaling in early neurogenesis and provide insight into the molecular mechanisms underlying neurodevelopmental disorders and neurodegenerative diseases. STEM CELLS 2012;30:510-524