ABSTRACT
During development, the growth of neural processes is regulated by an array of cellular and molecular mechanisms which influence growth rate, direction and branching. Recently, many members of the TNF superfamily have been shown to be key regulators of neurite growth during development. The founder member of this family, TNFα can both promote and inhibit neurite growth depending on the cellular context. Specifically, transmembrane TNFα promotes neurite growth, while soluble TNFα inhibits it. While the growth promoting effects of TNFα are restricted to a defined developmental window of early postnatal development, whether the growth inhibitory effects of soluble TNFα occur throughout development is unknown. In this study we used the extensively studied, well characterised neurons of the superior cervical ganglion to show that the growth inhibitory effects of soluble TNFα are restricted to a specific period of late embryonic and early postnatal development. Furthermore, we show that this growth inhibitory effect of soluble TNFα requires NF-κB signalling at all developmental stages at which soluble TNFα inhibits neurite growth. These findings raise the possibility that increases in the amount of soluble TNFα in vivo, for example as a result of maternal inflammation, could negatively affect neurite growth in developing neurons at specific stages of development.
Subject(s)
Neurites/drug effects , Neurogenesis , Sympathetic Nervous System/cytology , Tumor Necrosis Factor-alpha/pharmacology , Animals , Cells, Cultured , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Neurites/metabolism , Neurites/physiology , Rats , Rats, Sprague-Dawley , Sympathetic Nervous System/embryology , Sympathetic Nervous System/growth & developmentABSTRACT
Several secreted proteins facilitate the growth and guidance of sympathetic axons to their target organs during development. Here we show that IL-1ß, a key regulator of inflammation in the immune system, inhibits axonal growth and branching from cultured sympathetic neurons at a stage in development when their axons are ramifying within their targets in vivo. IL-1ß is synthesised in sympathetic ganglia and its targets at this stage, and IL-1ß protein is detectable in the axons and perikarya of the innervating neurons. It acts directly on developing axons to inhibit their growth via NF-κB signalling. These findings show that IL-1ß is a novel locally, and target-derived factor that can regulate the extent of sympathetic axon growth during the late embryonic and early postnatal period in developing rat sympathetic neurons.
