Brain-specific Drp1 regulates postsynaptic endocytosis and dendrite formation independently of mitochondrial division
Brain-specific Drp1 regulates postsynaptic endocytosis and dendrite formation independently of mitochondrial division
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DOI：
10.7554/elife.44739
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发表时间：
2019-10-11
期刊：
影响因子：
7.7
通讯作者：
Sesak, Hiromi
中科院分区：
文献类型：
--
作者：
Itoh, Kie;Murata, Daisuke;Sesak, Hiromi
动力相关蛋白 1 (Drp1) 将线粒体作为机械化学 GTP 酶进行分裂。然而，Drp1 在线粒体分裂之外的功能很大程度上未知。通过 mRNA 剪接产生多种 Drp1 同工型。其中一种异构体 Drp1(ABCD) 包含所有四个替代外显子，并且在大脑中特异性表达。在这里，我们使用 shRNA 的异构体特异性敲除和 CRISPR/Cas9 的异构体特异性敲除研究了培养物和动物系统中小鼠神经元中 Drp1(ABCD) 的功能。我们发现 Drp1(ABCD) 的表达在出生后大脑发育过程中被诱导。 Drp1(ABCD) 富含树突棘，通过将内吞区定位在突触后密度来调节突触后网格蛋白介导的内吞作用，与线粒体分裂无关。 Drp1(ABCD) 缺失促进神经元异位树突的形成，并增强小鼠的感觉运动门控行为。这些数据表明 Drp1(ABCD) 控制突触后内吞作用、神经元形态和脑功能。
Dynamin-related protein 1 (Drp1) divides mitochondria as a mechano-chemical GTPase. However, the function of Drp1 beyond mitochondrial division is largely unknown. Multiple Drp1 isoforms are produced through mRNA splicing. One such isoform, Drp1(ABCD), contains all four alternative exons and is specifically expressed in the brain. Here, we studied the function of Drp1(ABCD) in mouse neurons in both culture and animal systems using isoform-specific knockdown by shRNA and isoform-specific knockout by CRISPR/Cas9. We found that the expression of Drp1(ABCD) is induced during postnatal brain development. Drp1(ABCD) is enriched in dendritic spines and regulates postsynaptic clathrin-mediated endocytosis by positioning the endocytic zone at the postsynaptic density, independently of mitochondrial division. Drp1(ABCD) loss promotes the formation of ectopic dendrites in neurons and enhanced sensorimotor gating behavior in mice. These data reveal that Drp1(ABCD) controls postsynaptic endocytosis, neuronal morphology and brain function.