Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon, South Korea.
Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, South Korea.
Mol Brain. 2020 Jul 25;13(1):105. doi: 10.1186/s13041-020-00644-y.
Proper dendrite morphogenesis and neuronal migration are crucial for cerebral cortex development and neural circuit formation. In this study, we sought to determine if the histone deacetylase HDAC6 plays a role in dendrite development and neuronal migration of pyramidal neurons during cerebral cortex development. It was observed that knockdown of HDAC6 leads to defective dendrite morphogenesis and abnormal Golgi polarization in vitro, and the expression of wild type cortactin or deacetyl-mimetic cortactin 9KR rescued the defective phenotypes of the HDAC6 knockdown neurons. This suggests that HDAC6 promotes dendritic growth and Golgi polarization through cortactin deacetylation in vitro. We also demonstrated that ectopic expression of SIRT2, a cytoplasmic NAD - dependent deacetylase, suppresses the defects of HDAC6 knockdown neurons. These results indicate that HDAC6 and SIRT2 may be functionally redundant during dendrite development. Neurons transfected with both HDAC6 and SIRT2 shRNA or acetyl-mimetic cortactin 9KQ showed slow radial migration compared to the control cells during cerebral cortex development. Furthermore, a large portion of cortactin 9KQ-expressing pyramidal neurons at layer II/III in the cerebral cortex failed to form an apical dendrite toward the pial surface and had an increased number of primary dendrites, and the percentage of neurons with dendritic Golgi decreased in cortactin 9KQ-expressing cells, compared to control neurons. Taken together, this study suggests that HDAC6 and SIRT2 regulate neuronal migration and dendrite development through cortactin deacetylation in vivo.
适当的树突形态发生和神经元迁移对于大脑皮层发育和神经回路形成至关重要。在这项研究中，我们试图确定组蛋白去乙酰化酶 HDAC6 是否在大脑皮层发育过程中对锥体神经元的树突发育和神经元迁移起作用。观察到 HDAC6 的敲低导致体外树突形态发生缺陷和高尔基极化异常，野生型皮质肌动蛋白或去乙酰化模拟皮质肌动蛋白 9KR 的表达挽救了 HDAC6 敲低神经元的缺陷表型。这表明 HDAC6 通过体外的皮质肌动蛋白去乙酰化促进树突生长和高尔基极化。我们还证明细胞质 NAD 依赖性去乙酰化酶 SIRT2 的异位表达抑制了 HDAC6 敲低神经元的缺陷。这些结果表明 HDAC6 和 SIRT2 在树突发育过程中可能具有功能冗余性。在大脑皮层发育过程中，与对照细胞相比，转染了 HDAC6 和 SIRT2 shRNA 或乙酰化模拟皮质肌动蛋白 9KQ 的神经元表现出较慢的放射状迁移。此外，与对照神经元相比，在大脑皮层 II/III 层中表达皮质肌动蛋白 9KQ 的大部分锥体神经元未能朝向软脑膜表面形成顶树突，并且初级树突数量增加，表达皮质肌动蛋白 9KQ 的细胞中的树突高尔基的神经元百分比降低。总之，这项研究表明，HDAC6 和 SIRT2 通过体内的皮质肌动蛋白去乙酰化调节神经元迁移和树突发育。
