Computational simulations reveal that Abl activity controls cohesiveness of actin networks in growth cones.
Computational simulations reveal that Abl activity controls cohesiveness of actin networks in growth cones.
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DOI：
10.1091/mbc.e21-11-0535
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发表时间：
2022-09-15
影响因子：
3.3
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中科院分区：
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对生长轴突的广泛研究揭示了许多指导神经元形态发生的单个成分和蛋白质相互作用。然而，尽管如此，我们对这种纳米尺度的生物化学产生多微米尺度的轴突生长和体内引导的细胞生物学的紧急机制缺乏任何清晰的认识。为了解决这个问题，我们使用计算机模拟软件（MEDYAN）研究了Abl信号通路的下游效应，该软件解释了活性聚合物的机械化学动力学。先前的研究表明，两种Abl效应物Arp2/3和Enabled在依赖Abl的轴突引导决策中起作用。我们现在发现Abl主要通过激活Arp2/3来改变肌动蛋白结构，而Enabled发挥的作用更有限。我们的模拟表明，模拟适度水平的Abl活性与通过活体野生型轴突中肌动蛋白的实时成像实验获得的肌动蛋白谱具有惊人的相似性。此外，通过图形理论的丝-丝接触分析，我们发现模拟Abl过度活跃的网络（增强的Arp2/3）被分割成更小的肌动蛋白结构域，这些结构域彼此之间的相互作用较弱，这与体内Abl过表达时观察到的肌动蛋白碎片化模式一致。两个扰动模拟进一步证实，高arp2 /3的肌动蛋白网络是机械断开的，无法对扰动产生内聚响应。综上所述，这些数据提供了一幅分子水平的图像，说明轴突细胞骨架的大规模组织是如何从肌动蛋白网络的生物物理学中产生的。
Extensive studies of growing axons have revealed many individual components and protein interactions that guide neuronal morphogenesis. Despite this, however, we lack any clear picture of the emergent mechanism by which this nanometer-scale biochemistry generates the multimicron-scale morphology and cell biology of axon growth and guidance in vivo. To address this, we studied the downstream effects of the Abl signaling pathway using a computer simulation software (MEDYAN) that accounts for mechanochemical dynamics of active polymers. Previous studies implicate two Abl effectors, Arp2/3 and Enabled, in Abl-dependent axon guidance decisions. We now find that Abl alters actin architecture primarily by activating Arp2/3, while Enabled plays a more limited role. Our simulations show that simulations mimicking modest levels of Abl activity bear striking similarity to actin profiles obtained experimentally from live imaging of actin in wild-type axons in vivo. Using a graph theoretical filament–filament contact analysis, moreover, we find that networks mimicking hyperactivity of Abl (enhanced Arp2/3) are fragmented into smaller domains of actin that interact weakly with each other, consistent with the pattern of actin fragmentation observed upon Abl overexpression in vivo. Two perturbative simulations further confirm that high-Arp2/3 actin networks are mechanically disconnected and fail to mount a cohesive response to perturbation. Taken together, these data provide a molecular-level picture of how the large-scale organization of the axonal cytoskeleton arises from the biophysics of actin networks.