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. So far, it has been assumed that cell death was relatively neglectable in this tissue both during larval stage and pupal stage, and as a result, the pattern of growth was usually attributed to the distribution of cell division. Here, using systematic mapping and registration combined with quantitative assessment of clone size and disappearance as well as live imaging, we outline a persistent pattern of cell death and clone elimination emerging in the larval wing disc and persisting during pupal wing morphogenesis. Local variation of cell death is associated with local variation of clone size, pointing to an impact of cell death on local growth that is not fully compensated by proliferation. Using morphometric analyses of adult wing shape and genetic perturbations, we provide evidence that patterned death locally and globally affects adult wing shape and size. This study describes a roadmap for precise assessment of the contribution of cell death to tissue shape and outlines an important instructive role of cell death in modulating quantitatively local growth and morphogenesis of a fast-growing tissue.

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. In this review, we illustrate this complexity of epithelial apoptosis regulation by describing these different layers of control, all demonstrating that local cell death probability is a complex emerging feature. We first focus on non-cell autonomous factors that can locally modulate the rate of cell death, including cell competition, mechanical input and geometry as well as systemic effects. We then describe the multiple feedback mechanisms generated by cell death itself. We also outline the multiple layers of regulation of epithelial cell death, including the coordination of extrusion and regulation occurring downstream of effector caspases. Eventually, we propose a roadmap to reach a more predictive understanding of cell death regulation in an epithelial context.