Septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation.
Septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation.
复制标题
DOI：
10.1038/ncomms3532
复制
发表时间：
2013
影响因子：
16.6
通讯作者：
Kinoshita, Makoto
中科院分区：
文献类型：
--
作者：
Ageta-Ishihara, Natsumi;Miyata, Takaki;Ohshima, Chika;Watanabe, Masahiko;Sato, Yoshikatsu;Hamamura, Yuki;Higashiyama, Tetsuya;Mazitschek, Ralph;Bito, Haruhiko;Kinoshita, Makoto
神经突生长需要微管蛋白和败蛋白这两种鸟嘌呤核苷酸结合蛋白聚合物。然而，这些细胞骨架系统是否以及如何协调尚不清楚。在这里，我们表明，当微管严重超乙酰化时，来自大脑皮质神经元的关键隔膜亚基SEPT7的急性敲除或敲除会损害围产期小鼠的半球间和脑脊髓轴突投射和树突发生。由此产生的微管超稳定和生长迟缓已在体外得到证实。 SEPT7 缺失与 α-微管蛋白脱乙酰酶 HDAC6 的药理学抑制之间的表型相似性表明，HDAC6 需要 SEPT7 不是因为其酶活性，而是为了与乙酰化 α-微管蛋白相关。这些和其他发现表明，septins 为 HDAC6 提供了物理支架，以实现有效的微管脱乙酰化，从而负向调节微管稳定性至神经突发生的最佳水平。我们的研究结果揭示了神经发育过程中 HDAC6 介导的两个普遍存在的细胞骨架系统耦合的潜在机制。 Septin 是一个杂聚 GTP/GDP 结合蛋白家族，与线虫的神经突发生有关。上田石原等人。研究表明，septins 也作为协调 HDAC6 介导的微管脱乙酰化的支架，促进发育中的小鼠大脑中的这一过程。
Neurite growth requires two guanine nucleotide-binding protein polymers of tubulins and septins. However, whether and how those cytoskeletal systems are coordinated was unknown. Here we show that the acute knockdown or knockout of the pivotal septin subunit SEPT7 from cerebrocortical neurons impairs their interhemispheric and cerebrospinal axon projections and dendritogenesis in perinatal mice, when the microtubules are severely hyperacetylated. The resulting hyperstabilization and growth retardation of microtubules are demonstrated in vitro. The phenotypic similarity between SEPT7 depletion and the pharmacological inhibition of α-tubulin deacetylase HDAC6 reveals that HDAC6 requires SEPT7 not for its enzymatic activity, but to associate with acetylated α-tubulin. These and other findings indicate that septins provide a physical scaffold for HDAC6 to achieve efficient microtubule deacetylation, thereby negatively regulating microtubule stability to an optimal level for neuritogenesis. Our findings shed light on the mechanisms underlying the HDAC6-mediated coupling of the two ubiquitous cytoskeletal systems during neural development. Septins are a family of heteropolymerizing GTP/GDP-binding proteins and are implicated in neuritogenesis in nematodes. Ageta-Ishihara et al. show that septins also facilitate this process in the developing mouse brain as scaffolds that coordinate HDAC6-mediated deacetylation of microtubules.
登录
查看更多内容
影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
14.9
作者：
Chung KH;Hart CC;Al-Bassam S;Avery A;Taylor J;Patel PD;Vojtek AB;Turner DL
通讯作者：
Turner DL
影响因子：
82.9
作者：
d'Ydewalle, Constantin;Krishnan, Jyothsna;Van Den Bosch, Ludo
通讯作者：
Van Den Bosch, Ludo
影响因子：
9.2
作者：
Mimori-Kiyosue, Y;Shiina, N;Tsukita, S
通讯作者：
Tsukita, S
影响因子：
64.5
作者：
Creppe, Catherine;Malinouskaya, Lina;Nguyen, Laurent
通讯作者：
Nguyen, Laurent