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The Journal of Neuroscience, August 13, 2008, 28(33):8246-8256; doi:10.1523/JNEUROSCI.1941-08.2008

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Development/Plasticity/Repair
Nuclear Factor B Signaling Either Stimulates or Inhibits Neurite Growth Depending on the Phosphorylation Status of p65/RelA

Humberto Gutierrez, ^* Gerard W. O'Keeffe, ^* Núria Gavaldà, Denis Gallagher, and Alun M. Davies

School of Biosciences, Cardiff University, Cardiff CF10 3US, United Kingdom

Correspondence should be addressed to Alun M. Davies, School of Biosciences, Cardiff University, Biomedical Building, Museum Avenue, Cardiff CF10 3US, UK. Email: daviesalun{at}cf.ac.uk

Nuclear factor B (NF-B) 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-B 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-B activation. In neonatal superior cervical ganglion sympathetic neurons, enhancing NF-B transcriptional activity by overexpressing either the p65 NF-B subunit or the IB kinase-β (IKKβ) subunit of the IB kinase complex, or by tumor necrosis factor (TNF) treatment, strongly inhibits neurite growth. Paradoxically in neonatal nodose ganglion sensory neurons, enhancing NF-B transcriptional activity by p65/p50 overexpression increases neurite growth, whereas enhancing NF-B transcriptional activity by IKKβ overexpression inhibits neurite growth. In addition to activating NF-B, IKKβ 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 IKKβ overexpression in both sensory and sympathetic neurons and the growth-inhibitory effects of TNF on sympathetic neurons. Furthermore, expression of a p65 S536D phosphomimetic mutant inhibits neurite growth from sensory neurons. These results demonstrate that NF-B can either stimulate or inhibit neurite growth in developing neurons depending on the phosphorylation status of p65.

Key words: axon; brain development; growth; phosphorylation; signal transduction; transcription factor

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Received Dec. 17, 2007; revised June 26, 2008; accepted July 3, 2008.

Correspondence should be addressed to Alun M. Davies, School of Biosciences, Cardiff University, Biomedical Building, Museum Avenue, Cardiff CF10 3US, UK. Email: daviesalun{at}cf.ac.uk

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