Rcan1 Deficiency Impairs Neuronal Migration and Causes Periventricular Heterotopia
Rcan1 Deficiency Impairs Neuronal Migration and Causes Periventricular Heterotopia
复制标题
Rcan1 缺陷会损害神经元迁移并导致脑室周围异位。
DOI：
10.1523/jneurosci.1003-14.2015
复制
发表时间：
2015-01-14
影响因子：
5.3
通讯作者：
Xiong, Zhi-Qi
中科院分区：
文献类型：
--
作者：
Li, Yang;Wang, Jie;Xiong, Zhi-Qi
脑室周围异位（PH）是一种皮层畸形，其特征是由于异常的神经元迁移导致神经元聚集在侧脑室。PH发病的分子机制尚不清楚。本研究表明，唐氏综合征相关基因钙调神经磷酸酶1 （Rcan1）的调节因子在大鼠皮层神经元的径向迁移中起重要作用。通过表达shRNA下调Rcan1可损伤神经祖细胞增殖，导致径向迁移和ph值缺陷。Rcan1的两种亚型（Rcan1-1和Rcan1-4）在大鼠脑中表达。Rcan1-1的耐shrna表达可以阻止Rcan1下调引起的迁移缺陷，但不能阻止Rcan1-4的表达。此外，我们发现Rcan1敲低显著降低了Flna的表达水平，Flna是细胞骨架重排和细胞迁移所必需的f -肌动蛋白交联蛋白，其突变导致人类最常见的双侧PH。最后，Rcan1敲低神经元中FLNA的过表达阻止了迁移异常。总之，这些发现表明Rcan1在调节径向迁移中作用于Flna的上游，并提示Rcan1-Flna通路的损伤可能是PH发病的基础。
Periventricular heterotopia (PH) is a cortical malformation characterized by aggregation of neurons lining the lateral ventricles due to abnormal neuronal migration. The molecular mechanism underlying the pathogenesis of PH is unclear. Here we show that Regulators of calcineurin 1 (Rcan1), a Down syndrome-related gene, plays an important role in radial migration of rat cortical neurons. Downregulation of Rcan1 by expressing shRNA impaired neural progenitor proliferation and led to defects in radial migration and PH. Two isoforms of Rcan1 (Rcan1-1 and Rcan1-4) are expressed in the rat brain. Migration defects due to downregulation of Rcan1 could be prevented by shRNA-resistant expression of Rcan1-1 but not Rcan1-4. Furthermore, we found that Rcan1 knockdown significantly decreased the expression level of Flna, an F-actin cross-linking protein essential for cytoskeleton rearrangement and cell migration, mutation of which causes the most common form of bilateral PH in humans. Finally, overexpression of FLNA in Rcan1 knockdown neurons prevented migration abnormalities. Together, these findings demonstrate that Rcan1 acts upstream from Flna in regulating radial migration and suggest that impairment of Rcan1-Flna pathway may underlie PH pathogenesis.