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The Journal of Neuroscience, February 11, 2009, 29(6):1599-1607; doi:10.1523/JNEUROSCI.3566-08.2009

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Development/Plasticity/Repair
Developmental Regulation of Sensory Neurite Growth by the Tumor Necrosis Factor Superfamily Member LIGHT

Núria Gavaldà, Humberto Gutierrez, and Alun M. Davies

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

Correspondence should be addressed to Alun M. Davies at the above address. Email: daviesalun{at}cf.ac.uk

In a PCR screen to identify novel cytokine candidates involved in neuronal development, we identified transcripts for the tumor necrosis factor superfamily member 14 (TNFSF14), generally known as LIGHT (lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells), together with its receptors, lymphotoxin-β receptor (LTβR) and TNF family receptor herpesvirus entry mediator (HVEM), in the experimentally tractable sensory neurons of the mouse nodose ganglion. Immunocytochemistry revealed coexpression of LIGHT and its receptors in all nodose ganglion neurons in neonates. Enhancing LIGHT signaling in these neurons by overexpressing LIGHT inhibited BDNF-promoted neurite growth during a narrow window of development in the immediate perinatal period without affecting neuronal survival. Overexpressing a LIGHT mutant that selectively activates HVEM, but not one that selectively activates LTβR, also inhibited BDNF-promoted growth, suggesting that neurite growth inhibition is mediated via HVEM. Blocking HVEM signaling by a function-blocking anti-HVEM antibody significantly enhanced neurite growth from nodose neurons grown both with and without BDNF. Likewise, neurons from LIGHT-deficient neonates exhibited significantly greater neurite growth than neurons from wild-type littermates in both the presence and absence of BDNF. LIGHT overexpression significantly inhibited NF-B activity, while preventing LIGHT-induced NF-B inhibition by overexpressing the p65 and p50 NF-B subunits prevented LIGHT-mediated growth inhibition. Together, these findings show that LIGHT/HVEM signaling negatively regulates neurite growth from developing sensory neurons via NF-B inhibition.

Key words: development; sensory neurons; TNF; neurite; neurotrophin; transcription factor; knock-out mice

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Received July 29, 2008; revised Dec. 3, 2008; accepted Dec. 23, 2008.

Correspondence should be addressed to Alun M. Davies at the above address. Email: daviesalun{at}cf.ac.uk

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