Both doublecortin and doublecortin-like kinase play a role in cortical interneuron migration
Both doublecortin and doublecortin-like kinase play a role in cortical interneuron migration
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DOI：
10.1523/jneurosci.4530-06.2007
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发表时间：
2007-04-04
影响因子：
5.3
通讯作者：
Parnavelas, John G.
中科院分区：
文献类型：
--
作者：
Friocourt, Gaelle;Liu, Judy S.;Parnavelas, John G.
I 型无脑畸形是一种以皮质层紊乱和脑回异常为特征的遗传性疾病，与严重的认知障碍和癫痫有关。 LIS1 和双皮质素 (DCX) 这两个基因已被证明与大部分 I 型无脑畸形病例有关。这两个基因都编码微管相关蛋白，这些蛋白已被证明对皮质锥体神经元的径向迁移很重要。为了研究 DCX 是否也在皮质中间神经元迁移中发挥作用，我们使用短发夹 RNA 灭活了大鼠胚胎第 17 天脑切片的神经节隆起中的 DCX。我们发现，当 DCX 表达被阻断时，中间神经元从神经节隆起到大脑皮层的迁移减慢但并非消失，类似于之前报道的径向神经元迁移。此外，DCX 缺陷的迁移中间神经元的过程比对照实验中的对应部分有更多的分支。 DCX 过表达可以挽救这些效应，证实 DCX 失活的特异性。当双皮质素样激酶（DCLK）（一种与 DCX 相关的微管相关蛋白）失活时，观察到中间神经元迁移的类似延迟，尽管细胞的形态未受影响。我们的发现证实了这些基因在中间神经元迁移中的重要性，即 Dcx、Dclk 和 Dcx/Dclk 突变小鼠的皮质中此类细胞的数量减少，且与野生型对照相比，它们的分布也不同。然而，每组突变动物的缺陷是不同的，这表明 DCX 和 DCLK 在皮质中间神经元迁移中具有不同的作用。
Type I lissencephaly, a genetic disease characterized by disorganized cortical layers and gyral abnormalities, is associated with severe cognitive impairment and epilepsy. Two genes, LIS1 and doublecortin (DCX), have been shown to be responsible for a large proportion of cases of type I lissencephaly. Both genes encode microtubule-associated proteins that have been shown to be important for radial migration of cortical pyramidal neurons. To investigate whether DCX also plays a role in cortical interneuron migration, we inactivated DCX in the ganglionic eminence of rat embryonic day 17 brain slices using short hairpin RNA. We found that, when DCX expression was blocked, the migration of interneurons from the ganglionic eminence to the cerebral cortex was slowed but not absent, similar to what had previously been reported for radial neuronal migration. In addition, the processes of DCX-deficient migrating interneurons were more branched than their counterparts in control experiments. These effects were rescued by DCX overexpression, confirming the specificity to DCX inactivation. A similar delay in interneuron migration was observed when Doublecortin-like kinase (DCLK), a microtubule-associated protein related to DCX, was inactivated, although the morphology of the cells was not affected. The importance of these genes in interneuron migration was confirmed by our finding that the cortices of Dcx, Dclk, and Dcx/Dclk mutant mice contained a reduced number of such cells in the cortex and their distribution was different compared with wild-type controls. However, the defect was different for each group of mutant animals, suggesting that DCX and DCLK have distinct roles in cortical interneuron migration.