Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo.
Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo.
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DOI：
10.1073/pnas.1711088114
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发表时间：
2017-10-24
影响因子：
11.1
通讯作者：
Monk KR
中科院分区：
文献类型：
--
作者：
Herbert AL;Fu MM;Drerup CM;Gray RS;Harty BL;Ackerman SD;O'Reilly-Pol T;Johnson SL;Nechiporuk AV;Barres BA;Monk KR
大脑中的少突胶质细胞将神经元轴突隔离在脂肪髓鞘层中以促进快速电信号。髓鞘碱性蛋白（MBP）是髓鞘的重要组成部分，在翻译成蛋白质之前以mRNA的形式被转运离开细胞体。在斑马鱼中，顺行运动驱动蛋白将mbp mRNA从细胞体中转运出去。我们现在发现了由逆行运动复合体动力蛋白/动力蛋白突变引起的斑马鱼髓鞘形成缺陷，动力蛋白/动力蛋白通常将货物运输回细胞体。然而，该突变体显示顺行mbp mRNA转运的缺陷。我们证实，在哺乳动物少突胶质细胞培养，药物抑制动力蛋白逮捕运输在两个方向，并降低MBP蛋白水平。因此，动力蛋白/动力肌动蛋白是矛盾的需要顺行mbp mRNA运输。中枢神经系统中的少突胶质细胞产生髓鞘，髓鞘是一种富含脂质的多层鞘，其围绕轴突并促进动作电位的快速传播。髓鞘的关键组分是髓鞘碱性蛋白（MBP），其表达需要顺行mRNA运输，然后在发育中的髓鞘处进行局部翻译。虽然顺行运动驱动蛋白KIF 1B参与了斑马鱼mbp mRNA的转运，但mbp的转运是如何被调节的还不完全清楚。从斑马鱼髓鞘形成缺陷的正向遗传筛选中，我们确定了actr 10的突变，actr 10编码动力蛋白的Arp 11亚基，动力蛋白是逆行运动动力蛋白的关键激活剂。无论是在斑马鱼的actr 10突变和药理学动力蛋白抑制的结果，在少突胶质细胞中的mbp mRNA的正确分布失败，表明逆行动力蛋白/动力蛋白复合物在顺行mbp mRNA运输的矛盾作用。为了解决这一现象背后的分子机制，我们从原代培养的哺乳动物少突胶质细胞中分离出标记Mbp的mRNA颗粒，以表明它们确实与逆行运动复合体相关。接下来，我们使用活细胞成像显示，急性药理学动力蛋白抑制迅速逮捕Mbp mRNA的运输在两个方向。慢性药理学动力蛋白抑制也废除MBP mRNA的分布和显着降低MBP蛋白水平。因此，这些细胞培养和整个动物的研究证明了逆行动力蛋白/动力肌动蛋白运动复合物在体内的顺行mbp mRNA运输和髓鞘形成的作用。
Oligodendrocytes in the brain insulate neuronal axons in layers of fatty myelin to facilitate fast electrical signaling. Myelin basic protein (MBP), an important myelin component, is transported as mRNA away from the cell body before being translated into protein. In zebrafish, the anterograde motor kinesin transports mbp mRNA away from the cell body. We now identify myelination defects in zebrafish caused by a mutation in the retrograde motor complex dynein/dynactin, which normally transports cargos back toward the cell body. However, this mutant displays defects in anterograde mbp mRNA transport. We confirm in mammalian oligodendrocyte cultures that drug inhibition of dynein arrests transport in both directions and decreases MBP protein levels. Thus, dynein/dynactin is paradoxically required for anterograde mbp mRNA transport. Oligodendrocytes in the central nervous system produce myelin, a lipid-rich, multilamellar sheath that surrounds axons and promotes the rapid propagation of action potentials. A critical component of myelin is myelin basic protein (MBP), expression of which requires anterograde mRNA transport followed by local translation at the developing myelin sheath. Although the anterograde motor kinesin KIF1B is involved in mbp mRNA transport in zebrafish, it is not entirely clear how mbp transport is regulated. From a forward genetic screen for myelination defects in zebrafish, we identified a mutation in actr10, which encodes the Arp11 subunit of dynactin, a critical activator of the retrograde motor dynein. Both the actr10 mutation and pharmacological dynein inhibition in zebrafish result in failure to properly distribute mbp mRNA in oligodendrocytes, indicating a paradoxical role for the retrograde dynein/dynactin complex in anterograde mbp mRNA transport. To address the molecular mechanism underlying this observation, we biochemically isolated reporter-tagged Mbp mRNA granules from primary cultured mammalian oligodendrocytes to show that they indeed associate with the retrograde motor complex. Next, we used live-cell imaging to show that acute pharmacological dynein inhibition quickly arrests Mbp mRNA transport in both directions. Chronic pharmacological dynein inhibition also abrogates Mbp mRNA distribution and dramatically decreases MBP protein levels. Thus, these cell culture and whole animal studies demonstrate a role for the retrograde dynein/dynactin motor complex in anterograde mbp mRNA transport and myelination in vivo.
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影响因子：
9.9
作者：
Harms, M. B.;Ori-McKenney, K. M.;Baloh, R. H.
通讯作者：
Baloh, R. H.
影响因子：
3.4
作者：
MacPhail, R. C.;Brooks, J.;Padilla, S.
通讯作者：
Padilla, S.
DOI：
10.1038/nrm2804
发表时间：
2009-12
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1126/science.1242939
发表时间：
2014-01-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Buxbaum AR;Wu B;Singer RH
通讯作者：
Singer RH
DOI：
10.1083/jcb.123.2.431
发表时间：
1993-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ainger K;Avossa D;Morgan F;Hill SJ;Barry C;Barbarese E;Carson JH
通讯作者：
Carson JH