Nuclear Factor κB Signaling Either Stimulates or Inhibits Neurite Growth Depending on the Phosphorylation Status of p65/RelA

Abstract

Nuclear factor kappaB (NF-kappaB) signaling is known to promote neurite growth from developing sensory neurons and to enhance the size and complexity of pyramidal neuron dendritic arbors in the developing cerebral cortex. In marked contrast, here we show that NF-kappaB signaling can also exert a potent inhibitory influence on neurite growth in certain neurons, and can either promote or inhibit neurite growth in the same neurons depending on the mechanism of NF-kappaB activation. In neonatal superior cervical ganglion sympathetic neurons, enhancing NF-kappaB transcriptional activity by overexpressing either the p65 NF-kappaB subunit or the IkappaB kinase-beta (IKKbeta) subunit of the IkappaB kinase complex, or by tumor necrosis factor alpha (TNFalpha) treatment, strongly inhibits neurite growth. Paradoxically in neonatal nodose ganglion sensory neurons, enhancing NF-kappaB transcriptional activity by p65/p50 overexpression increases neurite growth, whereas enhancing NF-kappaB transcriptional activity by IKKbeta overexpression inhibits neurite growth. In addition to activating NF-kappaB, IKKbeta overexpression leads to phosphorylation of p65 on serine 536. Blockade of serine 536 phosphorylation by a S536A-p65 mutant protein prevents the growth-inhibitory effects of IKKbeta overexpression in both sensory and sympathetic neurons and the growth-inhibitory effects of TNFalpha on sympathetic neurons. Furthermore, expression of a p65 S536D phosphomimetic mutant inhibits neurite growth from sensory neurons. These results demonstrate that NF-kappaB can either stimulate or inhibit neurite growth in developing neurons depending on the phosphorylation status of p65.