Antagonistic forces generated by cytoplasmic dynein and myosin-II during growth cone turning and axonal retraction
Antagonistic forces generated by cytoplasmic dynein and myosin-II during growth cone turning and axonal retraction
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DOI：
10.1111/j.1600-0854.2006.00476.x
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发表时间：
2006-10-01
期刊：
影响因子：
4.5
通讯作者：
Baas, Peter W.
中科院分区：
文献类型：
--
作者：
Myers, Kenneth A.;Tint, Irina;Baas, Peter W.
细胞质动力蛋白部分通过推动肌动蛋白细胞骨架将短微管运输到轴突下。最近的研究表明，类似的动力蛋白驱动的力量可能会冲击轴突内较长的微管。在这里，我们研究了这些力量在通过小干扰RNA部分耗尽动力蛋白重链(DHC)的神经元中对轴突回缩和生长锥转动的潜在作用。虽然DHC耗尽的轴突以正常速度生长，但它们对一氧化氮供体的反应比对照轴突收缩得更强劲，它们的生长锥体未能有效地对底物边界做出反应。动态微管末端的活细胞成像显示，DHC耗尽的生长锥体中的微管主要局限于中心区，极少数延伸到丝状足。即使在微管动力学受到抑制的情况下，DHC的耗竭也削弱了微管进入生长锥体外周区域的能力，这表明动力蛋白驱动的力对微管的分布起着直接作用。这些效应都被肌球蛋白-II力的抑制所逆转，众所周知，肌球蛋白-II力是生长锥体中肌动蛋白逆行流动的基础，以及轴突回缩期间皮质肌动蛋白的收缩能力。我们的结果与动力蛋白驱动的力使微管能够克服肌球蛋白II驱动的力的模型是一致的，无论是在轴索轴还是在生长锥内。这些动力蛋白驱动的力量与轴突收缩的趋势相反，并允许微管进入生长锥体的外围区域，以便它们可以入侵丝足。
Cytoplasmic dynein transports short microtubules down the axon in part by pushing against the actin cytoskeleton. Recent studies have suggested that comparable dynein-driven forces may impinge upon the longer microtubules within the axon. Here, we examined a potential role for these forces on axonal retraction and growth cone turning in neurons partially depleted of dynein heavy chain (DHC) by small interfering RNA. While DHC-depleted axons grew at normal rates, they retracted far more robustly in response to donors of nitric oxide than control axons, and their growth cones failed to efficiently turn in response to substrate borders. Live cell imaging of dynamic microtubule tips showed that microtubules in DHC-depleted growth cones were largely confined to the central zone, with very few extending into filopodia. Even under conditions of suppressed microtubule dynamics, DHC depletion impaired the capacity of microtubules to advance into the peripheral zone of the growth cone, indicating a direct role for dynein-driven forces on the distribution of the microtubules. These effects were all reversed by inhibition of myosin-II forces, which are known to underlie the retrograde flow of actin in the growth cone and the contractility of the cortical actin during axonal retraction. Our results are consistent with a model whereby dynein-driven forces enable microtubules to overcome myosin-II-driven forces, both in the axonal shaft and within the growth cone. These dynein-driven forces oppose the tendency of the axon to retract and permit microtubules to advance into the peripheral zone of the growth cone so that they can invade filopodia.