Src kinases relax adherens junctions between the neighbors of apoptotic cells to permit apical extrusion

Abstract

Epithelia can eliminate apoptotic cells by apical extrusion. This is a complex morphogenetic event where expulsion of the apoptotic cell is accompanied by rearrangement of its immediate neighbors to form a rosette. A key mechanism for extrusion is constriction of an actomyosin network that neighbor cells form at their interface with the apoptotic cell. Here we report a complementary process of cytoskeletal relaxation that occurs when cortical contractility is downregulated at the junctions between those neighbor cells themselves. This reflects a mechanosensitive Src family kinase (SFK) signaling pathway that is activated in neighbor cells when the apoptotic cell relaxes shortly after injury. Inhibiting SFK signaling blocks both the expulsion of apoptotic cells and rosette formation amongst their neighbor cells. This reveals the complex pattern of spatially-distinct contraction and relaxation that must be established in the neighboring epithelium for apoptotic cells to be extruded. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

Optogenetic activators of apoptosis, necroptosis and pyroptosis for probing cell death dynamics and bystander cell responses

“…What determines these differential fates remains to be identified, but it is conceivable that necrotic and apoptotic cells release different signals/molecules or present different mechanical stimuli that elicit differential responses in their neighbors. While our findings differ strikingly from several studies that report extrusion of apoptotic cells 28,[30][31][32][33]59,60,65,66 , these differences could be potentially due to different cell lines used, or the way cell death is induced.…”

“…Efferocytosis by non-professional phagocytes, including epithelial cells, has been reported as well 57 , but is less well understood as most epithelia, such as the gut epithelium, are thought to react to cell death by extruding dying cells 58 . For example, multiple in vitro studies clearly demonstrate extrusion of dying cells in response to different proapoptotic triggers, such as etoposide treatment 59,60 , UV illumination 28,32,61 or starvation 62 . Our results using single cell killing by optoCDEs in human epithelial cell culture and in zebrafish skin however reveal that the type of cell death a dying cell undergoes might have a critical role in determining its fate.…”

Actin-based force generation and cell adhesion in tissue morphogenesis

“…For example, unbalanced apical contractility (i.e., when a cell is more contractile than its neighbors) can induce basal epithelial cell extrusion, such as during Caenorhabditis elegans gastrulation 29,65 , Drosophila neuroblast ingression 66,67 , and Drosophila dorsal closure 68 . In cell culture, epithelial cell extrusion results when apical tension relaxes relative to neighboring cells, suggesting that the force imbalance is critical for a cell to leave the epithelium 69 . Consistent with the force balance argument, cell-autonomous actin-based protrusion causes apical emergence (i.e.…”

An asymmetric junctional mechanoresponse coordinates mitotic rounding with epithelial integrity

“…For determining recoil velocity, distances (d) between vertices of the ablated cell-cell contacts prior to (d( 0)) and following ablation (d(t)) were determined using ImageJ software and plotted as a function of time (f(t)) using Prism 8 software (GraphPad). Initial recoil velocities, as well as the ratio between junctional elasticity and viscosity of the media (k), were computed as described previously (Liang et al, 2016;Teo et al, 2020) by nonlinear regression of the data to the following equation:…”