Impaired Reelin-Dab1 Signaling Contributes to Neuronal Migration Deficits of Tuberous Sclerosis Complex.
Impaired Reelin-Dab1 Signaling Contributes to Neuronal Migration Deficits of Tuberous Sclerosis Complex.
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DOI：
10.1016/j.celrep.2015.07.013
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发表时间：
2015-08-11
期刊：
影响因子：
8.8
通讯作者：
Kim S
中科院分区：
文献类型：
--
作者：
Moon UY;Park JY;Park R;Cho JY;Hughes LJ;McKenna J 3rd;Goetzl L;Cho SH;Crino PB;Gambello MJ;Kim S
多发性硬化症（TSC）与神经发育异常有关，包括神经元迁移缺陷。然而，TSC中神经元迁移和最终定位的细胞信号传导机制的改变仍不清楚。我们详细的细胞分析表明，新生神经元中Tsc 2的减少会导致迁移神经元的主导过程异常，并伴有明显延迟的迁移。重要的是，我们证明了Reelin-Dab 1信号传导在TSC小鼠模型和TSC患者的皮质块茎中受到异常调节，这是由于E3泛素连接酶Cul 5（一种已知的pDab 1泛素化介质）的表达增强。同样地，通过Rheb过表达的mTORC 1激活产生类似的神经元和Reelin-Dab 1信号传导缺陷，并直接上调Cul 5表达。通过雷帕霉素处理或通过减少Cul 5来抑制mTORC 1在很大程度上恢复了正常的引导过程和迁移神经元的定位。因此，破坏的Reelin-Dab 1信号传导与TSC的神经元迁移缺陷密切相关。
Tuberous sclerosis complex (TSC) is associated with neurodevelopmental abnormalities, including defects in neuronal migration. However, the alterations in cell signaling mechanisms critical for migration and final positioning of neurons in TSC remain unclear. Our detailed cellular analyses reveal that reduced Tsc2 in newborn neurons causes abnormalities in leading processes of migrating neurons, accompanied by significantly delayed migration. Importantly, we demonstrate that Reelin-Dab1 signaling is aberrantly regulated in TSC mouse models and in cortical tubers from TSC patients owing to enhanced expression of the E3 ubiquitin ligase, Cul5, a known mediator of pDab1 ubiquitination. Likewise, mTORC1 activation by Rheb overexpression generates similar neuronal and Reelin-Dab1 signaling defects, and directly upregulates Cul5 expression. Inhibition of mTORC1 by rapamycin treatment or by reducing Cul5 largely restores normal leading processes and positioning of migrating neurons. Thus, disrupted Reelin-Dab1 signaling is critically involved in the neuronal migration defects of TSC.