An expanded view of cell competition.

Cell competition arises in heterogeneous tissues when neighbouring cells sense their relative fitness and undergo selection. It has been a challenge to define contexts in which cell competition is a physiologically relevant phenomenon and to understand the cellular features that underlie fitness and fitness sensing. Drawing on examples across a range of contexts and length scales, we illuminate molecular and cellular features that could underlie fitness in diverse tissue types and processes to promote and reinforce long-term maintenance of tissue function.

In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution.

The tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues, the mechanisms that result in only a small number of clones transforming into malignant tumours remain unknown. Here we develop an in vivo single-cell CRISPR strategy to systematically investigate tissue-wide clonal dynamics of the 150 most frequently mutated squamous cell carcinoma genes.

Relocation sustains intestinal stem-cell numbers.

A dynamic mode of stem-cell regulation has been discovered. Intestinal stem cells use migration to maintain a large pool of multifunctional cells, perhaps endowing the organ with robust responses to injury.

Stem cell progeny liaisons in regeneration.

Stem cells are the functional units of tissue repair but do not act alone. Studies on flatworms now reveal specialized populations of differentiated cells that transiently emerge to coordinate whole body regeneration. The stem cell-centric view of repair processes must be revised to account for the importance of cell fate dynamics beyond the niche.

Distinct modes of cell competition shape mammalian tissue morphogenesis.

Cell competition-the sensing and elimination of less fit 'loser' cells by neighbouring 'winner' cells-was first described in Drosophila. Although cell competition has been proposed as a selection mechanism to optimize tissue and organ development, its evolutionary generality remains unclear. Here, by using live imaging, lineage tracing, single-cell transcriptomics and genetics, we identify two cell competition mechanisms that sequentially shape and maintain the architecture of stratified tissue during skin development in mice.

Basal Cell-Extracellular Matrix Adhesion Regulates Force Transmission during Tissue Morphogenesis.

Tissue morphogenesis requires force-generating mechanisms to organize cells into complex structures. Although many such mechanisms have been characterized, we know little about how forces are integrated across developing tissues. We provide evidence that integrin-mediated cell-extracellular matrix (ECM) adhesion modulates the transmission of apically generated tension during dorsal closure (DC) in Drosophila.

The talin head domain reinforces integrin-mediated adhesion by promoting adhesion complex stability and clustering.

Talin serves an essential function during integrin-mediated adhesion in linking integrins to actin via the intracellular adhesion complex. In addition, the N-terminal head domain of talin regulates the affinity of integrins for their ECM-ligands, a process known as inside-out activation. We previously showed that in Drosophila, mutating the integrin binding site in the talin head domain resulted in weakened adhesion to the ECM.

Talin autoinhibition is required for morphogenesis.

The establishment of a multicellular body plan requires coordinating changes in cell adhesion and the cytoskeleton to ensure proper cell shape and position within a tissue. Cell adhesion to the extracellular matrix (ECM) via integrins plays diverse, essential roles during animal embryogenesis and therefore must be precisely regulated. Talin, a FERM-domain containing protein, forms a direct link between integrin adhesion receptors and the actin cytoskeleton and is an important regulator of integrin function.

Zasp regulates integrin activation.

Integrins are heterodimeric adhesion receptors that link the extracellular matrix (ECM) to the cytoskeleton. Binding of the scaffold protein, talin, to the cytoplasmic tail of β-integrin causes a conformational change of the extracellular domains of the integrin heterodimer, thus allowing high-affinity binding of ECM ligands. This essential process is called integrin activation.

Mechanical force regulates integrin turnover in Drosophila in vivo.

Regulated assembly and disassembly, or turnover, of integrin-mediated cell-extracellular matrix (ECM) adhesions is essential for dynamic cell movements and long-term tissue maintenance. For example, in Drosophila, misregulation of integrin turnover disrupts muscle-tendon attachment at myotendinous junctions (MTJs). We demonstrate that mechanical force, which modulates integrin activity, also regulates integrin and intracellular adhesion complex (IAC) turnover in vivo.

In vivo functional analysis reveals specific roles for the integrin-binding sites of talin.

Adhesion receptors play diverse roles during animal development and require precise spatiotemporal regulation, which is achieved through the activity of their binding partners. Integrins, adhesion receptors that mediate cell attachment to the extracellular matrix (ECM), connect to the intracellular environment through the cytoplasmic adapter protein talin. Talin has two essential functions: orchestrating the assembly of the intracellular adhesion complex (IAC), which associates with integrin, and regulating the affinity of integrins for the ECM.

Distinct developmental roles for direct and indirect talin-mediated linkage to actin.

Transmembrane adhesion receptors, such as integrins, mediate cell adhesion by interacting with intracellular proteins that connect to the cytoskeleton. Talin, one such linker protein, is essential to connect extracellular matrix-bound integrins to the cytoskeleton. Talin can connect to the cytoskeleton either directly, through its actin-binding motifs, or indirectly, by recruiting other actin-binding proteins.

Integrin-mediated adhesion maintains sarcomeric integrity.

Integrin-mediated adhesion to the ECM is essential for normal development of animal tissues. During muscle development, integrins provide the structural stability required to construct such a highly tensile, force generating tissue. Mutations that disrupt integrin-mediated adhesion in skeletal muscles give rise to a myopathy in humans and mice.

Integrin-mediated adhesion and stem-cell-niche interactions.

The regulation of stem cell behavior and maintenance typically involves the integration of both intrinsic and extrinsic cues. One such external cue, integrin-mediated cell adhesion to the extracellular matrix, plays an important part in regulating stem cell function and maintenance. In particular, integrins help define and shape the microenvironment in which stem cells are found: the stem cell niche.