Integrin adhesion drives the emergent polarization of active cytoskeletal stresses to pattern cell delamination

Abstract

Tissue patterning relies on cellular reorganization through the interplay between signaling pathways and mechanical stresses. Their integration and spatiotemporal coordination remain poorly understood. Here we investigate the mechanisms driving the dynamics of cell delamination, diversely deployed to extrude dead cells or specify distinct cell fates. We show that a local mechanical stimulus (subcellular laser perturbation) releases cellular prestress and triggers cell delamination in the amnioserosa during Drosophila dorsal closure, which, like spontaneous delamination, results in the rearrangement of nearest neighbors around the delaminating cell into a rosette. We demonstrate that a sequence of "emergent cytoskeletal polarities" in the nearest neighbors (directed myosin flows, lamellipodial growth, polarized actomyosin collars, microtubule asters), triggered by the mechanical stimulus and dependent on integrin adhesion, generate active stresses that drive delamination. We interpret these patterns in the language of active gels as asters formed by active force dipoles involving surface and body stresses generated by each cell and liken delamination to mechanical yielding that ensues when these stresses exceed a threshold. We suggest that differential contributions of adhesion, cytoskeletal, and external stresses must underlie differences in spatial pattern.cell extrusion | cell mechanics | tissue dynamics | wound-healing T he establishment and maintenance of tissue pattern depends on cellular interactions mediated predominantly by the cadherin and integrin families of adhesion molecules. Their coupling to the (active) cytoskeleton enables mechanochemical transduction and through it the ability of cells in dynamic epithelia to actively generate, transmit, and sense mechanical stresses (1-4). How mechanochemical transduction is spatiotemporally regulated to facilitate the complex and diverse spatial patterns of tissues is poorly understood.The amnioserosa (AS) during dorsal closure in Drosophila provides a rich heterogeneity of patterned cell behaviors and an attractive in vivo model to address the interplay between adhesion, active forces, and cell behavior. Genetic and large-scale laser perturbations have shown that it is the principal driving force for dorsal closure (5-8). Its contraction by apical constriction [at ≈2 μm 2 /s during mid to late dorsal closure (5)] over the yolk cell helps establish continuity of the epidermis through the meeting of the leading edge cells of the epidermis to which it is bound (6,7,9). A small fraction of AS cells is also extruded seemingly stochastically from the epithelium (delamination) without compromising its integrity and is necessary for the timely completion of dorsal closure (9, 10). What underlies this stochasticity and how it is accommodated within the stereotypical dynamics of the AS remain unclear. Because delamination is commonly used to eliminate dead cells or to single out cells to adopt distinct fates, and is misregulated in cancers, an understanding of its pat...

Integration of actomyosin contractility with cell-cell adhesion during dorsal closure

“…We noticed that the tears within the AS usually appear at sites of cell delamination. It is known that around 10% of AS cells are eliminated from the epithelium through a mechanism involving cytoskeletal rearrangements in the delaminating cell and also in its nearest neighbours (Meghana et al, 2011;Muliyil et al, 2011;Toyama et al, 2008). We observe that the number of cell delamination events in mbs 541 mutant embryos increases, but this is not due to an increase in cell density (Fig.…”

Local, cell-nonautonomous feedback regulation of myosin dynamics patterns transitions in cell behavior: a role for tension and geometry?

“…Cell expansion alters cell morphology of the nearest neighbors such that they become progressively shorter along the radial axis and stretched along the azimuthal axis. The constriction that follows is associated with stretch and shortening in the opposite axes, radial and azimuthal respectively, of the nearest neighbors (Figure 3, A1–A4; Meghana et al. , 2011).…”

Actin Rings of Power

“…In general, cells can be extruded either apically into the surrounding lumen or basally into the underlying tissue and/or extracellular matrix ( Figure 6). In Drosophila, for instance, cells extrude predominantly basally, in a process known as cell delamination (Marinari et al, 2012;Meghana et al, 2011;Muliyil et al, 2011), whereas in vertebrates, epithelial cells are predominantly extruded apically. The direction in which cells are extruded can have major consequences for their fate.…”