MUNC18-1 gene abnormalities are involved in neurodevelopmental disorders through defective cortical architecture during brain development.
MUNC18-1 gene abnormalities are involved in neurodevelopmental disorders through defective cortical architecture during brain development.
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DOI：
10.1186/s40478-017-0498-5
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发表时间：
2017-11-30
影响因子：
7.1
通讯作者：
Nagata KI
中科院分区：
文献类型：
--
作者：
Hamada N;Iwamoto I;Tabata H;Nagata KI
虽然Munc 18 -1与Syntaxin 1相互作用并控制可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）复合物的形成，以调节发育神经元中的突触前囊泡融合，但该分子可能参与脑发育，因为其基因异常导致具有抑制爆发的早期婴儿癫痫性脑病（Ohtahara综合征）、新生儿癫痫性脑病和其他神经发育障碍。因此，我们分析了Munc 18 -1在皮层发育过程中的生理意义。munc 18 -1-敲低损害小鼠皮质生成过程中皮质神经元定位。延时成像显示，错位是由于中间区和皮质板的径向迁移缺陷。值得注意的是，Syntaxin 1A对于Munc 18 -1下游的径向迁移至关重要。至于潜在的机制，Munc 18 -1-敲低皮质神经元阻碍后高尔基体囊泡运输和随后的囊泡融合在质膜在体内和体外，分别。值得注意的是，Syntaxin 1A沉默不影响后高尔基体囊泡运输。两者合计，Munc 18 -1被认为不仅通过调节质膜上的囊泡融合以将各种蛋白质分布在细胞表面上与径向纤维相互作用，而且还通过调节囊泡从高尔基体运输到质膜来调节径向迁移。虽然敲除实验表明Syntaxin 1A不参与囊泡运输，但它应该在Munc 18 -1的控制下调节随后的囊泡融合。这些观察结果可能有助于阐明皮层神经元径向迁移的机制。Munc 18 -1功能的破坏可能会导致皮质发生异常，从而导致Munc 18 -1基因异常的神经发育障碍。本文的在线版本（10.1186/s40478-017-0498-5）包含补充材料，可供授权用户使用。
While Munc18–1 interacts with Syntaxin1 and controls the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex to regulate presynaptic vesicle fusion in developed neurons, this molecule is likely to be involved in brain development since its gene abnormalities cause early infantile epileptic encephalopathy with suppression-burst (Ohtahara syndrome), neonatal epileptic encephalopathy and other neurodevelopmental disorders. We thus analyzed physiological significance of Munc18–1 during cortical development. Munc18–1-knockdown impaired cortical neuron positioning during mouse corticogenesis. Time-lapse imaging revealed that the mispositioning was attributable to defects in radial migration in the intermediate zone and cortical plate. Notably, Syntaxin1A was critical for radial migration downstream of Munc18–1. As for the underlying mechanism, Munc18–1-knockdown in cortical neurons hampered post-Golgi vesicle trafficking and subsequent vesicle fusion at the plasma membrane in vivo and in vitro, respectively. Notably, Syntaxin1A-silencing did not affect the post-Golgi vesicle trafficking. Taken together, Munc18–1 was suggested to regulate radial migration by modulating not only vesicle fusion at the plasma membrane to distribute various proteins on the cell surface for interaction with radial fibers, but also preceding vesicle transport from Golgi to the plasma membrane. Although knockdown experiments suggested that Syntaxin1A does not participate in the vesicle trafficking, it was supposed to regulate subsequent vesicle fusion under the control of Munc18–1. These observations may shed light on the mechanism governing radial migration of cortical neurons. Disruption of Munc18–1 function may result in the abnormal corticogenesis, leading to neurodevelopmental disorders with MUNC18–1 gene abnormalities. The online version of this article (10.1186/s40478-017-0498-5) contains supplementary material, which is available to authorized users.
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影响因子：
11.1
作者：
Inaguma, Yutaka;Hamada, Nanako;Tabata, Hidenori;Iwamoto, Ikuko;Mizuno, Makoto;Nishimura, Yoshiaki V.;Ito, Hidenori;Morishita, Rika;Suzuki, Motomasa;Ohno, Kinji;Kumagai, Toshiyuki;Nagata, Koh-ichi
通讯作者：
Nagata, Koh-ichi
影响因子：
3.3
作者：
Han, SH;Morgan, JI
通讯作者：
Morgan, JI
影响因子：
5.3
作者：
Law, Chris;Profes, Marcos Schaan;Kania, Artur
通讯作者：
Kania, Artur
影响因子：
8.8
作者：
Martin, Sally;Papadopulos, Andreas;Meunier, Frederic A.
通讯作者：
Meunier, Frederic A.
影响因子：
4.6
作者：
Goto M;Mizuno M;Matsumoto A;Yang Z;Jimbo EF;Tabata H;Yamagata T;Nagata KI
通讯作者：
Nagata KI