Actin capping protein regulates postsynaptic spine development through CPI-motif interactions

• Type of Material: Article
• Authors: Kenneth Myers, Emory University; Yanjie Fan, Emory University; Patrick McConnell, Washington University in St. Louis; John A Cooper, Washington University in St. Louis; James Zheng, Emory University
• Language: English
• Date: 2022-09-29
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Myers, Fan, McConnell, Cooper and Zheng.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fnmol.2022.1020949
• Title of Journal or Parent Work: FRONTIERS IN MOLECULAR NEUROSCIENCE
• Volume: 15
• Start Page: 1020949
• End Page: 1020949
• Grant/Funding Information: This research was supported in part by research grants from the National Institutes of Health to JZ (GM083889 and MH104632), to KM (MH120414), and to JC (GM118171 and GM144082), the University Research Committee of Emory University (KM), the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities, and the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454.
• Keywords: Science & Technology; MOTILITY; CapZ; CELL-MIGRATION; dendritic spine; SHANK; postsynaptic density; Neurosciences & Neurology; Neurosciences; EXPRESSION; DYNAMICS; Life Sciences & Biomedicine; SYNAPSE; ARP2/3 COMPLEX; synapse; Shank; MATURATION; Twinfilin; cytoskeleton; TWINFILIN; FILAMENT BARBED ENDS
• Research Categories: Biology, Cell; Chemistry, Biochemistry

Abstract

Dendritic spines are small actin-rich protrusions essential for the formation of functional circuits in the mammalian brain. During development, spines begin as dynamic filopodia-like protrusions that are then replaced by relatively stable spines containing an expanded head. Remodeling of the actin cytoskeleton plays a key role in the formation and modification of spine morphology, however many of the underlying regulatory mechanisms remain unclear. Capping protein (CP) is a major actin regulating protein that caps the barbed ends of actin filaments, and promotes the formation of dense branched actin networks. Knockdown of CP impairs the formation of mature spines, leading to an increase in the number of filopodia-like protrusions and defects in synaptic transmission. Here, we show that CP promotes the stabilization of dendritic protrusions, leading to the formation of stable mature spines. However, the localization and function of CP in dendritic spines requires interactions with proteins containing a capping protein interaction (CPI) motif. We found that the CPI motif-containing protein Twinfilin-1 (Twf1) also localizes to spines where it plays a role in CP spine enrichment. The knockdown of Twf1 leads to an increase in the density of filopodia-like protrusions and a decrease in the stability of dendritic protrusions, similar to CP knockdown. Finally, we show that CP directly interacts with Shank and regulates its spine accumulation. These results suggest that spatiotemporal regulation of CP in spines not only controls the actin dynamics underlying the formation of stable postsynaptic spine structures, but also plays an important role in the assembly of the postsynaptic apparatus underlying synaptic function.