title: Emergence of large-scale cell morphology and movement from local actin filament growth dynamics.
abstract: Variations in cell migration and morphology are consequences of changes in underlying cytoskeletal organization and dynamics. We investigated how these large-scale cellular events emerge as direct consequences of small-scale cytoskeletal molecular activities. Because the properties of the actin cytoskeleton can be modulated by actin-remodeling proteins, we quantitatively examined how one such family of proteins, enabled/vasodilator-stimulated phosphoprotein (Ena/VASP), affects the migration and morphology of epithelial fish keratocytes. Keratocytes generally migrate persistently while exhibiting a characteristic smooth-edged "canoe" shape, but may also exhibit less regular morphologies and less persistent movement. When we observed that the smooth-edged canoe keratocyte morphology correlated with enrichment of Ena/VASP at the leading edge, we mislocalized and overexpressed Ena/VASP proteins and found that this led to changes in the morphology and movement persistence of cells within a population. Thus, local changes in actin filament dynamics due to Ena/VASP activity directly caused changes in cell morphology, which is coupled to the motile behavior of keratocytes. We also characterized the range of natural cell-to-cell variation within a population by using measurable morphological and behavioral features--cell shape, leading-edge shape, filamentous actin (F-actin) distribution, cell speed, and directional persistence--that we have found to correlate with each other to describe a spectrum of coordinated phenotypes based on Ena/VASP enrichment at the leading edge. This spectrum stretched from smooth-edged, canoe-shaped keratocytes--which had VASP highly enriched at their leading edges and migrated fast with straight trajectories--to more irregular, rounder cells migrating slower with less directional persistence and low levels of VASP at their leading edges. We developed a mathematical model that accounts for these coordinated cell-shape and behavior phenotypes as large-scale consequences of kinetic contributions of VASP to actin filament growth and protection from capping at the leading edge. This work shows that the local effects of actin-remodeling proteins on cytoskeletal dynamics and organization can manifest as global modifications of the shape and behavior of migrating cells and that mathematical modeling can elucidate these large-scale cell behaviors from knowledge of detailed multiscale protein interactions.
authors.affiliation: Department of Biochemistry, Stanford University, Stanford, California, United States of America.
authors.forename: Catherine I
authors.initials: CI
authors.lastname: Lacayo
authors.forename: Zachary
authors.initials: Z
authors.lastname: Pincus
authors.forename: Martijn M
authors.initials: MM
authors.lastname: VanDuijn
authors.forename: Cyrus A
authors.initials: CA
authors.lastname: Wilson
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Fletcher
authors.forename: Frank B
authors.initials: FB
authors.lastname: Gertler
authors.forename: Alex
authors.initials: A
authors.lastname: Mogilner
authors.forename: Julie A
authors.initials: JA
authors.lastname: Theriot
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D048430:Cell Shape / Q000502:physiology*; D002478:Cells, Cultured; D003599:Cytoskeleton; D005399:Fishes; D015603:Keratinocytes / Q000166:cytology; D008840:Microfilament Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein