NGF-promoted axon growth and target innervation requires GITRL-GITR signaling.
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.
O'Keeffe
Gerard W
GW
School of Biosciences, Biomedical Building, Museum Avenue, Cardiff, CF10 3US, UK.
Gutierrez
Humberto
H
Pandolfi
Pier Paolo
PP
Riccardi
Carlo
C
Davies
Alun M
AM
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005452:Fluoresceins / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000172:deficiency / Q000502:physiology*; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000166:cytology; D048069:Tumor Necrosis Factors / Q000172:deficiency / Q000378:metabolism*
D005452:Fluoresceins; D053450:Glucocorticoid-Induced TNFR-Related Protein; D008164:Luminescent Proteins; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors; C085925:calcein AM; D020932:Nerve Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3