Patterned apoptosis has an instructive role for local growth and tissue shape regulation in a fast-growing epithelium.

What regulates organ size and shape remains one fundamental mystery of modern biology. Research in this area has primarily focused on deciphering the regulation in time and space of growth and cell division, while the contribution of cell death has been overall neglected. This includes studies of the Drosophila wing, one of the best-characterized systems for the study of growth and patterning, undergoing massive growth during larval stage and important morphogenetic remodeling during pupal stage.

Staying away from the breaking point: Probing the limits of epithelial cell elimination.

Epithelial tissues are dramatically remodelled during embryogenesis and tissue homeostasis and yet need to maintain their sealing properties to sustain their barrier functions at any time. Part of these remodellings involve the elimination of a large proportion of cells through apoptosis. Cell extrusion, the remodelling steps leading to seamless dying cell expulsion, helps to maintain tissue cohesion.

Emerging roles and mechanisms of ERK pathway mechanosensing.

The coupling between mechanical forces and modulation of cell signalling pathways is essential for tissue plasticity and their adaptation to changing environments. Whilst the number of physiological and pathological relevant roles of mechanotransduction has been rapidly expanding over the last decade, studies have been mostly focussing on a limited number of mechanosensitive pathways, which include for instance Hippo/YAP/TAZ pathway, Wnt/β-catenin or the stretch-activated channel Piezo. However, the recent development and spreading of new live sensors has provided new insights into the contribution of ERK pathway in mechanosensing in various systems, which emerges now as a fast and modular mechanosensitive pathway.

Toward a predictive understanding of epithelial cell death.

Epithelial cell death is highly prevalent during development and tissue homeostasis. While we have a rather good understanding of the molecular regulators of programmed cell death, especially for apoptosis, we still fail to predict when, where, how many and which specific cells will die in a tissue. This likely relies on the much more complex picture of apoptosis regulation in a tissular and epithelial context, which entails cell autonomous but also non-cell autonomous factors, diverse feedback and multiple layers of regulation of the commitment to apoptosis.

DeXtrusion: automatic recognition of epithelial cell extrusion through machine learning in vivo.

Accurately counting and localising cellular events from movies is an important bottleneck of high-content tissue/embryo live imaging. Here, we propose a new methodology based on deep learning that allows automatic detection of cellular events and their precise xyt localisation on live fluorescent imaging movies without segmentation. We focused on the detection of cell extrusion, the expulsion of dying cells from the epithelial layer, and devised DeXtrusion: a pipeline based on recurrent neural networks for automatic detection of cell extrusion/cell death events in large movies of epithelia marked with cell contour.

Cell polarity and extrusion: How to polarize extrusion and extrude misspolarized cells?

The barrier function of epithelia is one of the cornerstones of the body plan organization of metazoans. It relies on the polarity of epithelial cells which organizes along the apico-basal axis the mechanical properties, signaling as well as transport. This barrier function is however constantly challenged by the fast turnover of epithelia occurring during morphogenesis or adult tissue homeostasis.

In vitro cellular reprogramming to model gonad development and its disorders.

During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs.

Keeping Cell Death Alive: An Introduction into the French Cell Death Research Network.

Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in , apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases.

Microtubule disassembly by caspases is an important rate-limiting step of cell extrusion.

The expulsion of dying epithelial cells requires well-orchestrated remodelling steps to maintain tissue sealing. This process, named cell extrusion, has been mostly analysed through the study of actomyosin regulation. Yet, the mechanistic relationship between caspase activation and cell extrusion is still poorly understood.

Collective effects in epithelial cell death and cell extrusion.

Programmed cell death, notably apoptosis, is an essential guardian of tissue homeostasis and an active contributor of organ shaping. While the regulation of apoptosis has been mostly analysed in the framework of a cell autonomous process, recent works highlighted important collective effects which can tune cell elimination. This is particularly relevant for epithelial cell death, which requires fine coordination with the neighbours in order to maintain tissue sealing during cell expulsion.

Cell competition: Bridging the scales through cell-based modeling.

Cell competition is a context-dependent, cell-elimination process that has been proposed to rely on several overlapping mechanisms. A new study combining cell-based modeling and quantitative microscopy data helps to evaluate the main contributors of mutant cell elimination.

LocalZProjector and DeProj: a toolbox for local 2D projection and accurate morphometrics of large 3D microscopy images.

Background: Quantitative imaging of epithelial tissues requires bioimage analysis tools that are widely applicable and accurate. In the case of imaging 3D tissues, a common preprocessing step consists of projecting the acquired 3D volume on a 2D plane mapping the tissue surface. While segmenting the tissue cells is amenable on 2D projections, it is still very difficult and cumbersome in 3D.

Robustness of epithelial sealing is an emerging property of local ERK feedback driven by cell elimination.

What regulates the spatiotemporal distribution of cell elimination in tissues remains largely unknown. This is particularly relevant for epithelia with high rates of cell elimination where simultaneous death of neighboring cells could impair epithelial sealing. Here, using the Drosophila pupal notum (a single-layer epithelium) and a new optogenetic tool to trigger caspase activation and cell extrusion, we first showed that death of clusters of at least three cells impaired epithelial sealing; yet, such clusters were almost never observed in vivo.

Cell Extrusion: Crowd Pushing and Sticky Neighbours.

Cell extrusion is a highly coordinated process allowing the removal of an epithelial cell from the tissue layer without disrupting its integrity. Two new studies shed new light on the complexity of cell-cell coordination at play during cell extrusion.

Multiple Influences of Mechanical Forces on Cell Competition.

Cell competition is a widespread process leading to the expansion of one cell population through the elimination and replacement of another. A large number of genetic alterations can lead to either competitive elimination of the mutated population or expansion of the mutated cells through the elimination of the neighbouring cells. Several processes have been proposed to participate in the preferential elimination of one cell population, including competition for limiting extracellular pro-survival factors, communication through direct cell-cell contact, or differential sensitivity to mechanical stress.

Solid stress, competition for space and cancer: The opposing roles of mechanical cell competition in tumour initiation and growth.

The regulation of cell growth, cell proliferation and cell death is at the basis of the homeostasis of tissues. While they can be regulated by intrinsic and genetic factors, their response to external signals emanating from the local environment is also essential for tissue homeostasis. Tumour initiation and progression is based on the misregulation of growth, proliferation and death mostly through the accumulation of genetic mutations.

Dying under pressure: cellular characterisation and in vivo functions of cell death induced by compaction.

Cells and tissues are exposed to multiple mechanical stresses during development, tissue homoeostasis and diseases. While we start to have an extensive understanding of the influence of mechanics on cell differentiation and proliferation, how excessive mechanical stresses can also lead to cell death and may be associated with pathologies has been much less explored so far. Recently, the development of new perturbative approaches allowing modulation of pressure and deformation of tissues has demonstrated that compaction (the reduction of tissue size or volume) can lead to cell elimination.

Competition for Space Induces Cell Elimination through Compaction-Driven ERK Downregulation.

The plasticity of developing tissues relies on the adjustment of cell survival and growth rate to environmental cues. This includes the effect of mechanical cues on cell survival. Accordingly, compaction of an epithelium can lead to cell extrusion and cell death.

Cell Competition: How to Take Over the Space Left by Your Neighbours.

Fast-growing cells can expand in a tissue by eliminating and replacing the neighbouring wild-type cells. A new study provides an elegant explanation for how cell elimination contributes to the preferential expansion of the invading population.

Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer.

Multicellular organisms evolved to resolve conflicts between individual cells, protecting the internal organization of the individual. This is illustrated by cell competition, a process that eliminates suboptimal cells from growing tissues by apoptosis. Since its early characterization in Drosophila an increasing number of conditions have been associated with competition, and mounting evidence demonstrates conservation of this process.

How to be in a good shape? The influence of clone morphology on cell competition.

Cell competition is a conserved mechanism where slow proliferating cells (so called losers) are eliminated by faster proliferating neighbors (so called winners) through apoptosis.(1) It is an important process which prevents developmental malformations and maintains tissue fitness in aging adults.(2) Recently, we have shown that the probability of elimination of loser cells correlates with the surface of contact between losers and winners in Myc-induced competition.

Tissue Crowding Induces Caspase-Dependent Competition for Space.

Regulation of tissue size requires fine tuning at the single-cell level of proliferation rate, cell volume, and cell death. Whereas the adjustment of proliferation and growth has been widely studied [1-5], the contribution of cell death and its adjustment to tissue-scale parameters have been so far much less explored. Recently, it was shown that epithelial cells could be eliminated by live-cell delamination in response to an increase of cell density [6].

Cell mixing induced by myc is required for competitive tissue invasion and destruction.

Cell-cell intercalation is used in several developmental processes to shape the normal body plan. There is no clear evidence that intercalation is involved in pathologies. Here we use the proto-oncogene myc to study a process analogous to early phase of tumour expansion: myc-induced cell competition.

Oscillation and polarity of E-cadherin asymmetries control actomyosin flow patterns during morphogenesis.

Actomyosin flows are involved in a variety of cellular processes, including cytokinesis, cell migration, polarization, and morphogenesis. In epithelia, flow polarization orients cell deformations. It is unclear, however, how flows are polarized and how global patterns of junction remodeling emerge from flow polarization locally.