Article abstract
Nature Neuroscience 11, 135 - 142 (2007)
Published online: 6 January 2008 | doi:10.1038/nn2034
NGF-promoted axon growth and target innervation requires GITRL-GITR signaling
Gerard W O'Keeffe1, Humberto Gutierrez1, Pier Paolo Pandolfi2, Carlo Riccardi3 & Alun M Davies1
Abstract
Nerve growth factor (NGF) has an important role in regulating sympathetic neuron survival and target field innervation during development. Here we show that glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR), a member of the TNF superfamily, and its ligand (GITRL) are co-expressed in mouse sympathetic neurons when their axons are innervating their targets under the influence of target-derived NGF. In culture, GITRL enhanced NGF-promoted neurite growth from neonatal sympathetic neurons, and preventing GITR-GITRL interaction in these neurons or knocking down GITR inhibited NGF-promoted neurite growth without affecting neuronal survival. Tnfrsf18-/- (Gitr) neonates have reduced sympathetic innervation density in vivo compared with Gitr+/+ littermates. GITR activation is required for the phosphorylation of extracellular signal–regulated kinases 1 and 2 by NGF that is necessary for neurite growth. Our results reveal a previously unknown signaling loop in developing sympathetic neurons that is crucial for NGF-dependent axon growth and target innervation.
- School of Biosciences, Biomedical Building, Museum Avenue, Cardiff, CF10 3US, UK.
- Cancer Genetics Program, and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
- Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Perugia, Via del Giochetto, 06100 Perugia, Italy.
Correspondence to: Alun M Davies1 e-mail: daviesalun@cf.ac.uk
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