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基因产物STIL对树突棘形成至关重要。

The Gene Product STIL Is Essential for Dendritic Spine Formation.

作者信息

Matsuki Tohru, Tabata Hidenori, Ueda Masashi, Ito Hideaki, Nagata Koh-Ichi, Tsuneura Yumi, Eda Shima, Kasai Kenji, Nakayama Atsuo

机构信息

Department of Cellular Pathology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai 480-0392, Aichi, Japan.

Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai 480-0392, Aichi, Japan.

出版信息

Cells. 2025 Jan 7;14(2):62. doi: 10.3390/cells14020062.

DOI:10.3390/cells14020062
PMID:39851490
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11764357/
Abstract

Dendritic spine formation/maintenance is highly dependent on actin cytoskeletal dynamics, which is regulated by small GTPases Rac1 and Cdc42 through their downstream p21-activated kinase/LIM-kinase-I/cofilin pathway. ARHGEF7, also known as ß-PIX, is a guanine nucleotide exchange factor for Rac1 and Cdc42, thereby activating Rac1/Cdc42 and the downstream pathway, leading to the upregulation of spine formation/maintenance. We found that STIL, one of the primary microcephaly gene products, is associated with ARHGEF7 in dendritic spines and that knockdown of resulted in a significant reduction in dendritic spines in neurons both in vitro and in vivo. Rescue experiments indicated that the STIL requirement for spine formation/maintenance depended on its coiled coil domain that mediates the association with ARHGEF7. The overexpression of Rac1/Cdc42 compensated for the spine reduction caused by STIL knockdown. FRET experiments showed that Rac activation is impaired in STIL knockdown neurons. Chemical long-term potentiation, which triggers Rac activation, promoted STIL accumulation in the spine and its association with ARHGEF7. The dynamics of these proteins further supported their coordinated involvement in spine formation/maintenance. Based on these findings, we concluded that the centrosomal protein STIL is a novel regulatory factor essential for spine formation/maintenance by activating Rac and its downstream pathway, possibly through the association with ARHGEF7.

摘要

树突棘的形成/维持高度依赖于肌动蛋白细胞骨架动力学，而这是由小GTP酶Rac1和Cdc42通过其下游的p21激活激酶/LIM激酶-I/丝切蛋白途径来调节的。ARHGEF7，也被称为β-PIX，是Rac1和Cdc42的鸟嘌呤核苷酸交换因子，从而激活Rac1/Cdc42及其下游途径，导致树突棘形成/维持的上调。我们发现，原发性小头症基因产物之一STIL在树突棘中与ARHGEF7相关联，并且敲低STIL会导致体外和体内神经元中树突棘显著减少。挽救实验表明，STIL对树突棘形成/维持的需求取决于其介导与ARHGEF7关联的卷曲螺旋结构域。Rac1/Cdc42的过表达补偿了由STIL敲低引起的树突棘减少。荧光共振能量转移实验表明，在敲低STIL的神经元中Rac激活受损。触发Rac激活的化学性长时程增强促进了STIL在树突棘中的积累及其与ARHGEF7的关联。这些蛋白质的动态变化进一步支持了它们在树突棘形成/维持中的协同作用。基于这些发现，我们得出结论，中心体蛋白STIL是通过激活Rac及其下游途径，可能通过与ARHGEF7的关联，对树突棘形成/维持至关重要的新型调节因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/317088c05318/cells-14-00062-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/a426316c68f0/cells-14-00062-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/636b82057367/cells-14-00062-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/c3b76dc8f57d/cells-14-00062-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/00a606e20bae/cells-14-00062-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/f02c708c0fc5/cells-14-00062-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/eca02f0730b9/cells-14-00062-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/317088c05318/cells-14-00062-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/a426316c68f0/cells-14-00062-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/636b82057367/cells-14-00062-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/c3b76dc8f57d/cells-14-00062-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/00a606e20bae/cells-14-00062-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/f02c708c0fc5/cells-14-00062-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/eca02f0730b9/cells-14-00062-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ece/11764357/317088c05318/cells-14-00062-g007.jpg

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