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.
| Original language | English (US) |
|---|---|
| Journal | PLoS Biology |
| Volume | 5 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2007 |
Fingerprint
ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
Cite this
Emergence of large-scale cell morphology and movement from local actin filament growth dynamics. / Lacayo, Catherine I.; Pincus, Zachary; VanDuijn, Martijn M.; Wilson, Cyrus A.; Fletcher, Daniel A.; Gertler, Frank B.; Mogilner, Alex; Theriot, Julie A.
In: PLoS Biology, Vol. 5, No. 9, 09.2007.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Emergence of large-scale cell morphology and movement from local actin filament growth dynamics.
AU - Lacayo, Catherine I.
AU - Pincus, Zachary
AU - VanDuijn, Martijn M.
AU - Wilson, Cyrus A.
AU - Fletcher, Daniel A.
AU - Gertler, Frank B.
AU - Mogilner, Alex
AU - Theriot, Julie A.
PY - 2007/9
Y1 - 2007/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=38449110129&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38449110129&partnerID=8YFLogxK
U2 - 10.1371/journal.pbio.0050233
DO - 10.1371/journal.pbio.0050233
M3 - Article
C2 - 17760506
AN - SCOPUS:34548475260
VL - 5
JO - PLoS Biology
JF - PLoS Biology
SN - 1544-9173
IS - 9
ER -