Neuregulins (NRGs) are EGF-like ligands associated with cognitive disorders. Unprocessed proNRG3 is cleaved by BACE1 to generate the mature membrane-bound NRG3 ligand, but the subcellular site of proNRG3 cleavage, mechanisms underlying its transport into axons, and presynaptic accumulation remain unknown. Using an optogenetic proNRG3 cleavage reporter (LA143-NRG3), we investigate the spatial-temporal dynamics of NRG3 processing and sorting in neurons. In dark conditions, unprocessed LA143-NRG3 is retained in the trans-Golgi network but, upon photoactivation, is cleaved by BACE1 and released from the TGN. Mature NRG3 then emerges on the somatodendritic plasma membrane from where it is re-endocytosed and anterogradely transported on Rab4+ vesicles into axons via transcytosis. By contrast, the BACE1 substrate APP is sorted into axons on Rab11+ vesicles. Lastly, by a mechanism we denote “trans-synaptic retention,” NRG3 accumulates at presynaptic terminals by stable interaction with its receptor ErbB4 on postsynaptic GABAergic interneurons. We propose that trans-synaptic retention may account for polarized expression of other neuronal transmembrane ligands and receptors.

中文翻译：

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突触后 ErbB4 的转胞吞作用和跨突触保留是 NRG3 轴突积累的基础

神经调节蛋白 (NRG) 是与认知障碍相关的 EGF 样配体。未加工的 proNRG3 被 BACE1 裂解，生成成熟的膜结合 NRG3 配体，但 proNRG3 裂解的亚细胞位点、其转运到轴突的机制以及突触前积累仍然未知。使用光遗传学 proNRG3 裂解报告基因 (LA143-NRG3)，我们研究了神经元中 NRG3 处理和分类的时空动态。在黑暗条件下，未加工的 LA143-NRG3 保留在跨高尔基体网络中，但在光激活后被 BACE1 裂解并从 TGN 中释放。然后成熟的 NRG3 出现在体细胞树突质膜上，从那里它被重新内吞并通过转胞吞作用在 Rab4+ 囊泡上顺行转运到轴突中。相比之下，BACE1 底物 APP 被分类到 Rab11+ 囊泡上的轴突中。最后，通过我们称为“跨突触保留”的机制，NRG3 通过与其突触后 GABA 能中间神经元上的受体 ErbB4 稳定相互作用而在突触前末端积累。我们认为跨突触保留可能是其他神经元跨膜配体和受体的极化表达的原因。