Tau, XMAP215/Msps and Eb1 co-operate interdependently to regulate microtubule polymerisation and bundle formation in axons.
Tau, XMAP215/Msps and Eb1 co-operate interdependently to regulate microtubule polymerisation and bundle formation in axons.
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DOI：
10.1371/journal.pgen.1009647
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发表时间：
2021-07
期刊：
影响因子：
4.5
通讯作者：
Prokop A
中科院分区：
文献类型：
--
作者：
Hahn I;Voelzmann A;Parkin J;Fülle JB;Slater PG;Lowery LA;Sanchez-Soriano N;Prokop A
微管的形成和维持需要它们的聚合，但人们对这种聚合在细胞中是如何调节的知之甚少。聚焦于果蝇和非洲爪哇神经元轴突中的基本微管束，我们表明正端支架Eb1、聚合酶XMAP215/MSPs和晶格结合蛋白Tau相互依赖地合作，促进轴突发育和维持过程中的微管聚合和束组织。Eb1和XMAP215/MSPs相互促进对方在聚合微管加端的定位。Tau在微管晶格上竞争Eb1结合，从而防止Eb1顶端池的耗尽。这三个因素在基因上相互作用，并显示出共同的突变表型：轴突生长、彗星大小、彗星数量和彗星速度减少，以及平行微管束显著退化为无序的卷曲构象。这种微管卷曲是由Eb1加端耗尽引起的，它损害了spectraplakin介导的将微管延伸到平行束的引导。我们的研究表明，Eb1、XMAP215/MSPs和Tau在微管聚合和束组织的调节过程中协同作用，为发育和退行性轴突病理提供了新的概念性解释。轴突是神经细胞的长达一米的突起，构成了连接我们神经系统的电缆。一旦建立起来，它们必须在人类体内存活一个世纪。轴突的不适当伸展会导致神经发育缺陷，而与年龄或疾病相关的神经变性通常始于轴突。轴突的结构和功能依赖于被称为微管的丝状聚合物束。这些束沿着轴突核心运行，它们的破坏与轴突衰退有关。这些轴突微管束是如何形成和动态维持的，目前还知之甚少。我们通过研究不同类别的微管结合蛋白如何调控这些过程来弥合这一知识鸿沟。在这里，我们展示了三种功能截然不同的蛋白质，Eb1，XMAP215和Tau，如何错综复杂地合作，促进在轴突发育和维持过程中形成新微管的聚合过程。如果任何一种蛋白质功能失调，聚合反应就会减慢，新形成的微管就不能排列成合适的束状。这些发现为微管束的衰退提供了新的解释，因此轴突也是如此。为了揭开这些机制，我们使用果蝇作为生物医学发现的强大有机体。然后，我们展示了同样的机制在青蛙轴突中起作用，这表明它们可能也适用于人类。
The formation and maintenance of microtubules requires their polymerisation, but little is known about how this polymerisation is regulated in cells. Focussing on the essential microtubule bundles in axons of Drosophila and Xenopus neurons, we show that the plus-end scaffold Eb1, the polymerase XMAP215/Msps and the lattice-binder Tau co-operate interdependently to promote microtubule polymerisation and bundle organisation during axon development and maintenance. Eb1 and XMAP215/Msps promote each other’s localisation at polymerising microtubule plus-ends. Tau outcompetes Eb1-binding along microtubule lattices, thus preventing depletion of Eb1 tip pools. The three factors genetically interact and show shared mutant phenotypes: reductions in axon growth, comet sizes, comet numbers and comet velocities, as well as prominent deterioration of parallel microtubule bundles into disorganised curled conformations. This microtubule curling is caused by Eb1 plus-end depletion which impairs spectraplakin-mediated guidance of extending microtubules into parallel bundles. Our demonstration that Eb1, XMAP215/Msps and Tau co-operate during the regulation of microtubule polymerisation and bundle organisation, offers new conceptual explanations for developmental and degenerative axon pathologies. Axons are the up-to-meter-long processes of nerve cells that form the cables wiring our nervous system. Once established, they must survive for a century in humans. Improper extension of axons leads to neurodevelopmental defects, and age- or disease-related neurodegeneration usually starts in axons. Axonal architecture and function depend on bundles of filamentous polymers, called microtubules. These bundles run all along the axonal core, and their disruption correlates with axon decay. How these axonal microtubule bundles are formed and dynamically maintained is little understood. We bridge this knowledge gap by studying how different classes of microtubule-binding proteins may regulate these processes. Here we show how three proteins of very different function, Eb1, XMAP215 and Tau, cooperate intricately to promote the polymerisation processes that form new microtubules during axon development and maintenance. If either protein is dysfunctional, polymerisation is slowed down and newly forming microtubules fail to align into proper bundles. These findings provide new explanations for the decay of microtubule bundles, hence axons. To unravel these mechanisms, we used the fruit fly as a powerful organism for biomedical discoveries. We then showed that the same mechanisms act in frog axons, suggesting they might apply also to humans.
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