Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
Life Sci Alliance. 2021 Sep 23;4(11). doi: 10.26508/lsa.202101092. Print 2021 Nov.
In neurons, the ER extends throughout all cellular processes, forming multiple contacts with the plasma membrane (PM) to fine-tune neuronal physiology. However, the mechanisms that regulate the distribution of neuronal ER-PM contacts are not known. Here, we used the DA9 motor neuron as our model system and found that neuronal ER-PM contacts are enriched in soma and dendrite and mostly absent in axons. Using forward genetic screen, we identified that the inositol 5-phosphatase, CIL-1 (human INPP5K), and the dynamin-like GTPase, ATLN-1 (human Atlastin-1), help to maintain the non-uniform, somatodendritic enrichment of neuronal ER-PM contacts. Mechanistically, CIL-1 acts upstream of ATLN-1 to maintain the balance between ER tubules and sheets. In mutants of CIL-1 or ATLN-1, ER sheets expand and invade into the axon. This is accompanied by the ectopic formation of axonal ER-PM contacts and defects in axon regeneration following laser-induced axotomy. As INPP5K and Atlastin-1 have been linked to neurological disorders, the unique distribution of neuronal ER-PM contacts maintained by these proteins may support neuronal resilience during the onset and progression of these diseases.
在神经元中，内质网（ER）延伸至所有细胞过程中，与质膜（PM）形成多个接触点，以精细调节神经元的生理机能。然而，调节神经元 ER-PM 接触点分布的机制尚不清楚。在这里，我们使用 DA9 运动神经元作为模型系统，发现神经元 ER-PM 接触点在胞体和树突中丰富，而在轴突中大部分不存在。通过正向遗传筛选，我们发现肌醇 5-磷酸酶 CIL-1（人类 INPP5K）和类似于 dynamin 的 GTPase ATLN-1（人类 Atlastin-1）有助于维持神经元 ER-PM 接触点的非均匀、胞体树突富集。从机制上讲，CIL-1 在上游作用于 ATLN-1，以维持 ER 小管和片层之间的平衡。在 CIL-1 或 ATLN-1 的突变体中，ER 片层扩张并侵入轴突。这伴随着轴突 ER-PM 接触点的异位形成和激光诱导的轴突切断后轴突再生的缺陷。由于 INPP5K 和 Atlastin-1 与神经疾病有关，这些蛋白维持的神经元 ER-PM 接触点的独特分布可能支持这些疾病发作和进展期间神经元的恢复能力。
