Division of Biological Sciences, Nagoya University Graduate School of Science, Nagoya 464-8602, Japan.
Nat Commun. 2013;4:2532. doi: 10.1038/ncomms3532.
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.
神经突生长需要两种微管蛋白和 septin 的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，我们显示在围产期小鼠中，大脑皮质神经元中关键 septin 亚基 SEPT7 的急性敲低或敲除会损害它们的半球间和脑脊 axon 投射和树突发生，此时微管严重乙酰化。体外证明了微管的超稳定和生长迟缓。SEPT7 耗竭与 α-微管去乙酰化酶 HDAC6 的药理学抑制之间的表型相似性表明，HDAC6 需要 SEPT7 不是为了其酶活性，而是为了与乙酰化的 α-微管结合。这些和其他发现表明 septin 为 HDAC6 提供了一个物理支架，以实现有效的微管去乙酰化，从而负调控微管稳定性，使其达到有利于神经突发生的最佳水平。我们的研究结果揭示了在神经发育过程中 HDAC6 介导的两种普遍存在的细胞骨架系统偶联的机制。
