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Edited by Peter N. Devreotes, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved November 30, 2015 (received for review July 7, 2015)
Significance
Cells orient their motility along chemical gradients using sensitive measurements of the external environment, a process termed chemotaxis. How cells sense, respond to, and remember varying environmental stimuli is only just beginning to be understood. Here, we identify a directional memory in chemotactic neutrophil-like cells. This memory allows cells to orient in low signal gradients and even uniform environments. This memory can be modeled by distinct time scales of chemical sensing and cytoskeletal dynamics, pointing to a general strategy of separating time scales for robust behavioral dynamics in cellular systems. Disrupting specific long-lived molecular assemblies erases directional memory. These studies reveal a novel directional memory resulting from distinct molecular time scales and contributing to chemotactic robustness in migrating cells.
Abstract
Chemotaxis, the directional migration of cells in a chemical gradient, is robust to fluctuations associated with low chemical concentrations and dynamically changing gradients as well as high saturating chemical concentrations. Although a number of reports have identified cellular behavior consistent with a directional memory that could account for behavior in these complex environments, the quantitative and molecular details of such a memory process remain unknown. Using microfluidics to confine cellular motion to a 1D channel and control chemoattractant exposure, we observed directional memory in chemotactic neutrophil-like cells. We modeled this directional memory as a long-lived intracellular asymmetry that decays slower than observed membrane phospholipid signaling. Measurements of intracellular dynamics revealed that moesin at the cell rear is a long-lived element that when inhibited, results in a reduction of memory. Inhibition of ROCK (Rho-associated protein kinase), downstream of RhoA (Ras homolog gene family, member A), stabilized moesin and directional memory while depolymerization of microtubules (MTs) disoriented moesin deposition and also reduced directional memory. Our study reveals that long-lived polarized cytoskeletal structures, specifically moesin, actomyosin, and MTs, provide a directional memory in neutrophil-like cells even as they respond on short time scales to external chemical cues.
Footnotes
↵1H.V.P.-M. and Y.M. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: lm{at}seas.harvard.edu or jagesh_shah{at}hms.harvard.edu.
Author contributions: H.V.P.-M., Y.M., L.M., and J.V.S. designed research; H.V.P.-M., Y.M., A.C., M.A.L., and L.M. performed research; H.V.P.-M., Y.M., M.W.D., D.I., and G.T.C. contributed new reagents/analytic tools; H.V.P.-M. and Y.M. analyzed data; and H.V.P.-M., Y.M., L.M., and J.V.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1513289113/-/DCSupplemental.
Directional memory in chemotactic cells
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