Creppe Catherine, Malinouskaya Lina, Volvert Marie-Laure, Gillard Magali, Close Pierre, Malaise Olivier, Laguesse Sophie, Cornez Isabelle, Rahmouni Souad, Ormenese Sandra, Belachew Shibeshih, Malgrange Brigitte, Chapelle Jean-Paul, Siebenlist Ulrich, Moonen Gustave, Chariot Alain, Nguyen Laurent
GIGA-Signal Transduction, University of Liege, C.H.U. Sart Tilman, 4000 Liège, Belgium.
Cell. 2009 Feb 6;136(3):551-64. doi: 10.1016/j.cell.2008.11.043. Epub 2009 Jan 29.
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.
皮质投射神经元的产生依赖于径向迁移与分支的协调。在此，我们报告多亚基组蛋白乙酰转移酶延伸因子复合物（其有助于转录延伸）也调节投射神经元的成熟。实际上，其支架亚基（Elp1）或催化亚基（Elp3）的细胞自主沉默会延迟投射神经元的迁移并损害其分支。引人注目的是，延伸因子有缺陷的神经元显示出乙酰化α-微管蛋白水平降低。通过表达不可乙酰化的α-微管蛋白突变体来降低α-微管蛋白乙酰化会导致皮质神经元出现类似缺陷，并表明α-微管蛋白是Elp3的作用靶点。体外实验证明Elp3促进该底物的乙酰化并抵消HDAC6介导的去乙酰化，这进一步支持了这一观点。我们的结果揭示α-微管蛋白是延伸因子复合物的作用靶点，并表明其乙酰化的严格调控是皮质投射神经元成熟的基础。
