The Golgi-associated microtubule cross-linking protein MTCL2 promotes the multipolar extension of dendrites in cerebellar granule neurons.

Mari Minekawa, Atsushi Suzuki
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Abstract

The dynamic regulation of neuronal polarity is essential for establishing neural networks during brain development. The primary culture of rodent neurons recapitulates several aspects of this polarity regulation and thus provides powerful tools for revealing the cellular and molecular mechanisms underlying axon specification and neuronal migration. However, little is known about how preexisting bipolarity breaks to form multipolar dendrites. Here, we demonstrated that the Golgi-associated, microtubule (MT) cross-linking protein MTCL2 plays an essential role in this type of polarity change observed in the differentiation of cerebellar granule neurons (CGNs). MTCL2 is highly expressed in CGNs and exhibited gradual accumulation in dendrites in parallel to their polarity development. MTCL2 depletion resulted in the generation of longer and fewer dendrites by suppressing the bipolar-to-multipolar transition of dendrite extension observed in the normal polarization process. During this process, the Golgi apparatus changes its localization from the base of the preexisting bipolar neurites to the lateral or apical side of the nucleus, where it associates closely with the MT cage wrapping the nucleus. The resulting upward extension of the Golgi apparatus is tightly coupled with randomization of its position in x-y plane. Knockdown/rescue experiments demonstrated that MTCL2 promotes these changes in Golgi position in an MT- and Golgi-binding activity-dependent manner. These results suggest that MTCL2 promotes the development of multipolar short dendrites by sequestering the Golgi apparatus from the base of preexisting neurites, enabling its random movements around nuclei.
高尔基相关微管交联蛋白MTCL2促进小脑颗粒神经元树突的多极延伸
神经元极性的动态调控对大脑发育过程中神经网络的建立至关重要。啮齿类神经元的原代培养再现了这种极性调控的多个方面,因此为揭示轴突规格化和神经元迁移的细胞和分子机制提供了强有力的工具。然而,人们对已有的双极性如何断裂以形成多极树突知之甚少。在这里,我们证明了在小脑颗粒神经元(CGNs)分化过程中观察到的这种极性变化中,与高尔基相关的微管(MT)交联蛋白MTCL2起着至关重要的作用。MTCL2在小脑颗粒神经元中高度表达,并在其极性发展的同时在树突中逐渐积累。抑制MTCL2可抑制正常极化过程中观察到的树突延伸的双极向多极转变,从而产生更长、更少的树突。在这一过程中,高尔基体改变了其定位,从先前存在的双极神经元基部转向核的外侧或顶端,在那里与包裹核的 MT 笼紧密结合。由此产生的高尔基体向上延伸与高尔基体在 x-y 平面上位置的随机化密切相关。基因敲除/拯救实验表明,MTCL2以依赖于MT和高尔基体结合活性的方式促进了高尔基体位置的这些变化。这些结果表明,MTCL2 通过将高尔基体从预先存在的神经元基部封闭起来,使其能够围绕核随机运动,从而促进了多极短树突的发育。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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