Elongator Controls the Migration and Differentiation of Cortical Neurons through Acetylation of α-Tubulin
Elongator Controls the Migration and Differentiation of Cortical Neurons through Acetylation of α-Tubulin
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DOI：
10.1016/j.cell.2008.11.043
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发表时间：
2009-02-06
期刊：
影响因子：
64.5
通讯作者：
Nguyen, Laurent
中科院分区：
文献类型：
--
作者：
Creppe, Catherine;Malinouskaya, Lina;Nguyen, Laurent
皮质投射神经元的产生依赖于径向迁移与分支的协调。在这里，我们报告了多亚单位组蛋白乙酰转移酶Elongator复合体，它有助于转录延长，也调节投射神经元的成熟。事实上，沉默其支架(Elp1)或催化亚单位(Elp3)细胞-自主延迟迁移并损害投射神经元的分支。令人惊讶的是，Elongator中有缺陷的神经元显示乙酰化α-微管蛋白水平降低。通过表达一个不可乙酰化的α-微管蛋白突变体来减少α-微管蛋白乙酰化导致皮质神经元中类似的缺陷，并表明α-微管蛋白是ELP3的靶标。在体外，Elp3促进了乙酰化并抵消了HDAC6介导的该底物的脱乙酰化，这进一步支持了这一点。我们的结果发现α-微管蛋白是Elongator复合体的靶标，并表明对其乙酰化的严格调控是皮质投射神经元成熟的基础。
The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here, we report that the multisubunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha-tubulin. Reduction of alpha-tubulin acetylation via expression of a nonacetylatable alpha-tubulin mutant leads to comparable defects in cortical neurons and suggests that alpha-tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha-tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons.