Department of Neuroscience, West Virginia University School of Medicine, Morgantown, WV 26506.
Biochemistry and Molecular Biology Graduate Program, West Virginia University School of Medicine, Morgantown, WV 26506.
eNeuro. 2020 Aug 20;7(4). doi: 10.1523/ENEURO.0132-20.2020. Print 2020 Jul/Aug.
Aberrant migration of inhibitory interneurons can alter the formation of cortical circuitry and lead to severe neurologic disorders including epilepsy, autism, and schizophrenia. However, mechanisms involved in directing the migration of interneurons remain incompletely understood. Using a mouse model, we performed live-cell confocal microscopy to explore the mechanisms by which the c-Jun NH-terminal kinase (JNK) pathway coordinates leading process branching and nucleokinesis, two cell biological processes that are essential for the guided migration of cortical interneurons. Pharmacological inhibition of JNK signaling disrupts the kinetics of leading process branching, rate and amplitude of nucleokinesis, and leads to the rearward mislocalization of the centrosome and primary cilium to the trailing process. Genetic loss of from interneurons also impairs leading process branching and nucleokinesis, suggesting that important mechanics of interneuron migration depend on the intrinsic activity of JNK. These findings highlight key roles for JNK signaling in leading process branching, nucleokinesis, and the trafficking of centrosomes and cilia during interneuron migration, and further implicates JNK signaling as an important mediator of cortical development.
抑制性中间神经元的异常迁移可能会改变皮质回路的形成，并导致严重的神经紊乱，包括癫痫、自闭症和精神分裂症。然而，指导中间神经元迁移的机制仍不完全清楚。我们使用小鼠模型，通过活细胞共聚焦显微镜来探索 c-Jun NH2 末端激酶（JNK）通路协调引导突起分支和核迁移这两个细胞生物学过程的机制，这两个过程对于皮质中间神经元的导向迁移至关重要。JNK 信号通路的药理学抑制会破坏引导突起分支的动力学、核迁移的速度和幅度，并导致中心体和初级纤毛向后定位到尾部突起。中间神经元中缺失也会损害引导突起分支和核迁移，这表明中间神经元迁移的重要力学取决于 JNK 的内在活性。这些发现强调了 JNK 信号在引导突起分支、核迁移以及中心体和纤毛在中间神经元迁移过程中的运输中的关键作用，并进一步表明 JNK 信号作为皮质发育的重要介质。
