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Research Article

Directional memory arises from long-lived cytoskeletal asymmetries in polarized chemotactic cells

Harrison V. Prentice-Mott, Yasmine Meroz, Andreas Carlson, Michael A. Levine, Michael W. Davidson, Daniel Irimia, Guillaume T. Charras, L. Mahadevan, and Jagesh V. Shah
  1. aDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115;
  2. bRenal Division, Brigham and Women’s Hospital, Boston, MA 02115;
  3. cPaulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
  4. dNational High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310;
  5. eDepartment of Surgery, Massachusetts General Hospital, Boston, MA 02129;
  6. fLondon Centre for Nanotechnology, University College London, London WC1H 0AH, United Kingdom;
  7. gDepartment of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom;
  8. hDepartment of Physics, Harvard University, Cambridge, MA 02138;
  9. iOrganismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138;
  10. jKavli Institute for Nanobio Science and Technology, Harvard University, Cambridge, MA 02138

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PNAS February 2, 2016 113 (5) 1267-1272; first published January 13, 2016; https://doi.org/10.1073/pnas.1513289113
Harrison V. Prentice-Mott
aDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115;
bRenal Division, Brigham and Women’s Hospital, Boston, MA 02115;
cPaulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
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Yasmine Meroz
cPaulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
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Andreas Carlson
cPaulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
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Michael A. Levine
aDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115;
bRenal Division, Brigham and Women’s Hospital, Boston, MA 02115;
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Michael W. Davidson
dNational High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310;
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Daniel Irimia
eDepartment of Surgery, Massachusetts General Hospital, Boston, MA 02129;
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Guillaume T. Charras
fLondon Centre for Nanotechnology, University College London, London WC1H 0AH, United Kingdom;
gDepartment of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom;
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L. Mahadevan
cPaulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
hDepartment of Physics, Harvard University, Cambridge, MA 02138;
iOrganismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138;
jKavli Institute for Nanobio Science and Technology, Harvard University, Cambridge, MA 02138
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  • For correspondence: lm@seas.harvard.edu jagesh_shah@hms.harvard.edu
Jagesh V. Shah
aDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115;
bRenal Division, Brigham and Women’s Hospital, Boston, MA 02115;
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  • For correspondence: lm@seas.harvard.edu jagesh_shah@hms.harvard.edu
  1. 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)

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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.

  • confined cell migration
  • moesin
  • microtubules
  • chemotaxis
  • cell polarization

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.

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Directional memory in chemotactic cells
Harrison V. Prentice-Mott, Yasmine Meroz, Andreas Carlson, Michael A. Levine, Michael W. Davidson, Daniel Irimia, Guillaume T. Charras, L. Mahadevan, Jagesh V. Shah
Proceedings of the National Academy of Sciences Feb 2016, 113 (5) 1267-1272; DOI: 10.1073/pnas.1513289113

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Directional memory in chemotactic cells
Harrison V. Prentice-Mott, Yasmine Meroz, Andreas Carlson, Michael A. Levine, Michael W. Davidson, Daniel Irimia, Guillaume T. Charras, L. Mahadevan, Jagesh V. Shah
Proceedings of the National Academy of Sciences Feb 2016, 113 (5) 1267-1272; DOI: 10.1073/pnas.1513289113
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