Leading edge maintenance in migrating cells is an emergent property of branched actin network growth
- Howard Hughes Medical Institute, University of Washington, United States
Abstract
Animal cell migration is predominantly driven by the coordinated, yet stochastic, polymerization of thousands of nanometer-scale actin filaments across micron-scale cell leading edges. It remains unclear how such inherently noisy processes generate robust cellular behavior. We employed high-speed imaging of migrating neutrophil-like HL-60 cells to explore the fine-scale shape fluctuations that emerge and relax throughout the process of leading edge maintenance. We then developed a minimal stochastic model of the leading edge that reproduces this stable relaxation behavior. Remarkably, we find lamellipodial stability naturally emerges from the interplay between branched actin network growth and leading edge shape - with no additional feedback required - based on a synergy between membrane-proximal branching and lateral spreading of filaments. These results thus demonstrate a novel biological noise-suppression mechanism based entirely on system geometry. Furthermore, our model suggests that the Arp2/3-mediated ~70‑80º branching angle optimally smooths lamellipodial shape, addressing its long-mysterious conservation from protists to mammals.
Data availability
Analysis and modeling code for this paper is available on the Theriot lab Gitlab:<https://gitlab.com/theriot_lab/leading-edge-stability-in-motile-cells-is-an-emergent-property-of-branched-actin-network-growth> under the MIT license. Figure data are available in the Source Data files. The large size of the raw video microscopy data (865 GB of image files in the Open Microscopy Environment OME-TIFF format) and the associated analyzed data (320 GB) prohibits their upload to a public repository. The complete raw and analyzed data files for one example experimental dataset and one example simulated dataset (corresponding to the data shown in Fig. 1a-f and Fig. 2c-j, respectively) are available on Figshare <https://figshare.com/projects/Leading_edge_stability_in_motile_cells_is_an_emergent_property_of_branched_actin_network_growth/132878>. Code to analyze this data are publicly available on Gitlab as noted above. Requests for additional raw or analyzed data should be sent to the corresponding author by email. Data will be made available in the form of a hard drive shipped by mail. There are no restrictions on who may access the data.
Article and author information
Author details
Funding
National Science Foundation
- Rikki M Garner
Howard Hughes Medical Institute
- Julie A Theriot
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Experiments using zebrafish larvae were approved by the University of Washington Institutional Animal Care and Use Committee (protocol 4427-01).
Copyright
© 2022, Garner & Theriot
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,325
- views
-
- 510
- downloads
-
- 19
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Leading edge maintenance in migrating cells is an emergent property of branched actin network growth
eLife 11:e74389.
https://doi.org/10.7554/eLife.74389
Further reading
-
- Cell Biology
The spatiotemporal transition of small GTPase Rab5 to Rab7 is crucial for early-to-late endosome maturation, yet the precise mechanism governing Rab5-to-Rab7 switching remains elusive. USP8, a ubiquitin-specific protease, plays a prominent role in the endosomal sorting of a wide range of transmembrane receptors and is a promising target in cancer therapy. Here, we identified that USP8 is recruited to Rab5-positive carriers by Rabex5, a guanine nucleotide exchange factor (GEF) for Rab5. The recruitment of USP8 dissociates Rabex5 from early endosomes (EEs) and meanwhile promotes the recruitment of the Rab7 GEF SAND-1/Mon1. In USP8-deficient cells, the level of active Rab5 is increased, while the Rab7 signal is decreased. As a result, enlarged EEs with abundant intraluminal vesicles accumulate and digestive lysosomes are rudimentary. Together, our results reveal an important and unexpected role of a deubiquitinating enzyme in endosome maturation.
-
- Cell Biology
- Developmental Biology
In most murine species, spermatozoa exhibit a falciform apical hook at the head end. The function of the sperm hook is not yet clearly understood. In this study, we investigate the role of the sperm hook in the migration of spermatozoa through the female reproductive tract in Mus musculus (C57BL/6), using a deep tissue imaging custom-built two-photon microscope. Through live reproductive tract imaging, we found evidence indicating that the sperm hook aids in the attachment of spermatozoa to the epithelium and facilitates interactions between spermatozoa and the epithelium during migration in the uterus and oviduct. We also observed synchronized sperm beating, which resulted from the spontaneous unidirectional rearrangement of spermatozoa in the uterus. Based on live imaging of spermatozoa-epithelium interaction dynamics, we propose that the sperm hook plays a crucial role in successful migration through the female reproductive tract by providing anchor-like mechanical support and facilitating interactions between spermatozoa and the female reproductive tract in the house mouse.
