NGF-promoted axon growth and target innervation requires GITRL-GITR signaling
Copyright policy )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.
- University of Turin Italy
- Harvard University United States
- Cardiff University United Kingdom
- University of Perugia Italy
- Beth Israel Deaconess Medical Center United States
570, Age Factors; Analysis of Variance; Animals; Newborn; Axons; Cells; Cultured; Embryo; Mammalian; Fluoresceins; Glucocorticoid-Induced TNFR-Related Protein; Luminescent Proteins; Mice; Inbred C57BL; Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nerve Growth Factor; Neurons; Phosphorylation; Signal Transduction; Superior Cervical Ganglion; Tumor Necrosis Factors, Neuronal Development, Superior Cervical Ganglion, SYMPATHETIC NEURON DEVELOPMENT; KAPPA-B ACTIVATION; NEUROTROPHIC FACTOR; TNF RECEPTOR; T-CELLS; SURVIVAL; PATHWAY; DEATH; TRKA; CONTRIBUTES, Mice, Glucocorticoid-Induced TNFR-Related Protein, Nerve Growth Factor, C141 - Developmental biology, Animals, Phosphorylation, Cells, Cultured, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Neurons, Analysis of Variance, Mitogen-Activated Protein Kinase 3, Age Factors, Embryo, Mammalian, Fluoresceins, Axons, Mice, Inbred C57BL, Luminescent Proteins, Animals, Newborn, Signal Transduction
570, Age Factors; Analysis of Variance; Animals; Newborn; Axons; Cells; Cultured; Embryo; Mammalian; Fluoresceins; Glucocorticoid-Induced TNFR-Related Protein; Luminescent Proteins; Mice; Inbred C57BL; Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nerve Growth Factor; Neurons; Phosphorylation; Signal Transduction; Superior Cervical Ganglion; Tumor Necrosis Factors, Neuronal Development, Superior Cervical Ganglion, SYMPATHETIC NEURON DEVELOPMENT; KAPPA-B ACTIVATION; NEUROTROPHIC FACTOR; TNF RECEPTOR; T-CELLS; SURVIVAL; PATHWAY; DEATH; TRKA; CONTRIBUTES, Mice, Glucocorticoid-Induced TNFR-Related Protein, Nerve Growth Factor, C141 - Developmental biology, Animals, Phosphorylation, Cells, Cultured, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Neurons, Analysis of Variance, Mitogen-Activated Protein Kinase 3, Age Factors, Embryo, Mammalian, Fluoresceins, Axons, Mice, Inbred C57BL, Luminescent Proteins, Animals, Newborn, Signal Transduction
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