MTSS1 Regulation of Actin-Nucleating Formin DAAM1 in Dendritic Filopodia Determines Final Dendritic Configuration of Purkinje Cells
MTSS1 Regulation of Actin-Nucleating Formin DAAM1 in Dendritic Filopodia Determines Final Dendritic Configuration of Purkinje Cells
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DOI：
10.1016/j.celrep.2018.06.013
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发表时间：
2018-07-03
期刊：
影响因子：
8.8
通讯作者：
Kengaku, Mineko
中科院分区：
文献类型：
--
作者：
Galbraith, Kelly Kawabata;Fujishima, Kazuto;Kengaku, Mineko
发育中的神经元的树突丝状伪足作为环境传感器，调节树突的空间组织和适当的突触前伙伴的目标。树突状丝状伪足的形态是由两个主要的成核途径，ARP 2/3复合物和formins组装的F-肌动蛋白的平衡决定的。反向BAR蛋白MTSS 1在浦肯野细胞（PC）中高度表达，并已显示上调ARP 2/3活性。MTSS 1条件性基因敲除小鼠中的PC表现出树突发育不全，这是由于发育过程中过度接触诱导的收缩。这种表型是伴随着延长的树突状丝状伪足和phenocopied的过度激活的肌动蛋白成核剂DAAM 1定位在PC树突状突起的尖端。包括单分子斑点显微镜在内的细胞生物学分析表明，MTSS 1的C末端与DAAM 1结合，并暂停DAAM 1介导的F-肌动蛋白聚合。因此，MTSS 1在树突状丝状伪足中起着双重作用，作为ARP 2/3抑制剂和ARP 2/3激活剂，决定最终的神经元形态。
Dendritic filopodia of developing neurons function as environmental sensors, regulating the spatial organization of dendrites and proper targeting to presynaptic partners. Dendritic filopodia morphology is determined by the balance of F-actin assembled via twomajor nucleating pathways, the ARP2/3 complex and formins. The inverse-BAR protein MTSS1 is highly expressed in Purkinje cells (PCs) and has been shown to upregulate ARP2/3 activity. PCs in MTSS1 conditional knockout mice showed dendrite hypoplasia due to excessive contact-induced retraction during development. This phenotype was concomitant with elongated dendritic filopodia and was phenocopied by overactivation of the actin nucleator formin DAAM1 localized in the tips of PC dendritic protrusions. Cell biology assays including single-molecule speckle microscopy demonstrated that MTSS1's C terminus binds to DAAM1 and paused DAAM1-mediated F-actin polymerization. Thus, MTSS1 plays a dual role as a formin inhibitor and ARP2/3 activator in dendritic filopodia, determining final neuronal morphology.