Developmental regulation of sensory neurite growth by the tumor necrosis factor superfamily member LIGHT.
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-beta receptor (LTbetaR) 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 LTbetaR, 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-kappaB activity, while preventing LIGHT-induced NF-kappaB inhibition by overexpressing the p65 and p50 NF-kappaB subunits prevented LIGHT-mediated growth inhibition. Together, these findings show that LIGHT/HVEM signaling negatively regulates neurite growth from developing sensory neurons via NF-kappaB inhibition.
Gavaldà
Núria
N
School of Biosciences, Cardiff University, Cardiff CF10 3US, United Kingdom.
Gutierrez
Humberto
H
Davies
Alun M
AM
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D015536:Down-Regulation; D006131:Growth Inhibitors / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family / Q000502:physiology; D016501:Neurites / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000502:physiology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000096:biosynthesis / Q000502:physiology*; D048069:Tumor Necrosis Factors / Q000096:biosynthesis / Q000502:physiology
D006131:Growth Inhibitors; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D048069:Tumor Necrosis Factors