NGF-promoted axon growth and target innervation requires GITRL-GITR signaling.
NGF-promoted axon growth and target innervation requires GITRL-GITR signaling.
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NGF 在发育过程中调节交感神经元存活和靶场神经支配中发挥着关键作用。在这里，我们展示了 TNF 超家族的成员 GITR 及其配体 GITRL 在小鼠交感神经元中共表达，当小鼠交感神经元的轴突在靶标衍生的 NGF 的影响下支配其靶标时。在培养中，GITRL 增强新生交感神经元 NGF 促进的神经突生长，并阻止这些神经元中 GITR-GITRL 相互作用，或者 GITR 敲低抑制 NGF 促进的神经突生长而不影响神经元存活。与 GITR+/+ 同窝出生的小鼠相比，GITR−/− 新生儿体内的交感神经支配密度降低。 NGF 磷酸化 ERK1/ERK2 需要 GITR 激活，而 NGF 是神经突生长所必需的。我们的结果揭示了发育中的交感神经元中存在一个完全未被怀疑的信号环路，这对于 NGF 依赖性轴突生长和目标神经支配至关重要。
NGF plays a pivotal role in regulating sympathetic neuron survival and target field innervation during development. Here we show that a member of the TNF superfamily, GITR 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 enhances NGF–promoted neurite growth from neonatal sympathetic neurons, and preventing GITR–GITRL interaction in these neurons or GITR knockdown inhibits NGF–promoted neurite growth without affecting neuronal survival. GITR−/− neonates have reduced sympathetic innervation density in vivo compared with GITR+/+ littermates. GITR activation is required for the phosphorylation of ERK1/ERK2 by NGF that is necessary for neurite growth. Our results reveal a completely unsuspected signalling loop in developing sympathetic neurons that is crucial for NGF–dependent axon growth and target innervation.