Postganglionic sympathetic neurons detect vascular derived neurotrophin 3 (NT3) via the axonally expressed receptor tyrosine kinase, TrkA, to promote chemo-attraction along intermediate targets. Once axons arrive to their final target, a structurally related neurotrophic factor, nerve growth factor (NGF), also acts through TrkA to promote final target innervation. Does TrkA signal differently at these different locales? We previously found that Coronin-1 is upregulated in sympathetic neurons upon exposure to NGF, thereby endowing the NGF-TrkA complex with new signaling capabilities (i.e. calcium signaling), which dampens axon growth and branching. Based on the notion that axons do not express functional levels of Coronin-1 prior to final target innervation, we developed an in vitro model for axon growth and branching along intermediate targets using Coro1a-/- neurons grown in NT3. We found that, similar to NGF-TrkA, NT3-TrkA is capable of inducing MAPK and PI3K in the presence or absence of Coronin-1. However, unlike NGF, NT3 does not induce calcium release from intracellular stores. Using a combination of pharmacology, knockout neurons and in vitro functional assays, we suggest that the NT3-TrkA complex uses Ras/MAPK and/or PI3K-AKT signaling to induce axon growth and inhibit axon branching along intermediate targets. However, in the presence of Coronin-1, these signaling pathways lose their ability to impact NT3 dependent axon growth or branching. This is consistent with a role for Coronin-1 as a molecular switch for axon behavior and suggests that Coronin-1 suppresses NT3 dependent axon behavior.

中文翻译：

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描绘沿着中间目标交感神经轴突生长的依赖神经营养蛋白3的信号通路。

节后交感神经元通过轴突表达的受体酪氨酸激酶TrkA检测血管源性神经营养蛋白3（NT3），以促进沿中间靶标的化学吸引。一旦轴突到达其最终靶标，结构相关的神经营养因子神经生长因子（NGF）也会通过TrkA促进最终靶标的神经支配。在这些不同的地区，TrkA信号是否不同？我们先前发现，在暴露于NGF后，交感神经元中Coronin-1上调，从而赋予NGF-TrkA复合物以新的信号传导功能（即钙信号传导），从而抑制轴突的生长和分支。基于这样的观念，即轴突在最终目标神经支配之前不表达Coronin-1的功能水平，我们使用在NT3中生长的Coro1a-/-神经元，开发了轴突生长和沿中间目标分支的体外模型。我们发现，类似于NGF-TrkA，NT3-TrkA能够在存在或不存在Coronin-1的情况下诱导MAPK和PI3K。但是，与NGF不同，NT3不会诱导钙从细胞内存储中释放。结合药理学，基因敲除神经元和体外功能测定，我们建议NT3-TrkA复合体使用Ras / MAPK和/或PI3K-AKT信号转导轴突生长并抑制轴突分支沿中间目标。但是，在Coronin-1的存在下，这些信号通路失去了影响依赖NT3的轴突生长或分支的能力。这与Coronin-1作为轴突行为的分子开关的作用是一致的，并且表明Coronin-1抑制了NT3依赖性轴突行为。