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 multi-micron 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.Highlight summaryHow do single-molecule dynamics produce multi-micron scale changes in actin organization in an extending axon? Comparison of computational simulations to in vivo data suggests that Abl kinase and Arp2/3 expand actomyosin networks by fragmenting into multiple domains, thus toggling the axon between states of local vs global internal connectivity.
33The fundamental problem in axon growth and guidance is to understand how cytoplasmic signaling 34 modulates the cytoskeleton to produce directed growth cone motility. We show here that the TSM1 35 pioneer axon of Drosophila extends by using Abl tyrosine kinase to shape the intrinsic fluctuations 36 of a mass of accumulated actin in the distal axon. The actin mass fluctuates stochastically in length, 37 but with a small, forward bias that drives the axon along its trajectory by promoting emergence of 38 protrusions in leading intervals where actin accumulates, and collapse of protrusions in lagging 39 intervals that actin has vacated. The actin mass is sculpted by Abl signaling, which 40 probabilistically modulates its key parameters -its width and internal disorder -to drive its 41 advance, while maintaining internal coherence. Comparison of TSM1 to other systems suggests 42 that the mechanism we demonstrate here is apt to be common among pioneer axons in many 43 organisms. 44 45 46
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