Differential growth triggers mechanical feedback that elevates Hippo signaling

Abstract

Mechanical stress can influence cell proliferation in vitro, but whether it makes a significant contribution to growth control in vivo, and how it is modulated and experienced by cells within developing tissues, has remained unclear. Here we report that differential growth reduces cytoskeletal tension along cell junctions within faster-growing cells. We propose a theoretical model to explain the observed reduction of tension within faster-growing clones, supporting it by computer simulations based on a generalized vertex model. This reduced tension modulates a biomechanical Hippo pathway, decreasing recruitment of Ajuba LIM protein and the Hippo pathway kinase Warts, and decreasing the activity of the growth-promoting transcription factor Yorkie. These observations provide a specific mechanism for a mechanical feedback that contributes to evenly distributed growth, and we show that genetically suppressing mechanical feedback alters patterns of cell proliferation in the developing Drosophila wing. By providing experimental support for the induction of mechanical stress by differential growth, and a molecular mechanism linking this stress to the regulation of growth in developing organs, our results confirm and extend the mechanical feedback hypothesis.Ajuba | tissue mechanics | Drosophila development | cytoskeleton | Hippo

BMP signaling controls buckling forces to modulate looping morphogenesis of the gut

“…A second intriguing possibility is that extensibility of the dorsal mesentery is itself regulated by stretch, and a loss of extensibility in RCAS-Noggin-infected embryos is secondary to a loss of stretch from diminished differential growth. There is growing evidence that tension in embryonic tissues can stimulate proliferation (24) and extracellular matrix production (25,26), orient cell divisions (27,28), drive gene expression (29,30), and alter cell morphology (31,32) and migration (33). It is unclear whether such mechanisms are at work in the developing gut.…”

Mechanisms of cell competition emerging from Drosophila studies

“…This appears to confer homeostatic feedback that is thought to promote uniform growth in normal development [30*]. Reduction of Yki activity occurs in the core of faster growing cell populations, such as wild type clones in Minute discs [30*], however, which does not correspond to the location of competitive cell death, close to the clone boundaries.…”

“…This appears to confer homeostatic feedback that is thought to promote uniform growth in normal development [30*]. Reduction of Yki activity occurs in the core of faster growing cell populations, such as wild type clones in Minute discs [30*], however, which does not correspond to the location of competitive cell death, close to the clone boundaries. How cell competition may be linked to compression is also questioned by evidence that soluble factors generated in mixed tissue cultures lacking epithelial organization and associated mechanics can mediate competition [31,22].…”

“…Cell competition is able to buffer organ size in response to hyperplasia induced by elevated Myc levels by reducing the contribution of unaffected cells [5]. Some competition phenomena may occur as consequences of homeostatic responses to mechanical forces in epithelia; these would be important to maintain homogenous organ growth and to dissipate stress within epithelia [30*]. Mutations in azot , a putative calcium binding protein gene induced by Myc cell competition, are reported to shorten lifespan and accumulate developmental defects, illustrating the possibility that cell competition optimizes progenitor cell pools during development and aging by eliminating defective cells [21*].…”

“…Not shown in panels (A) and (B) are the mechanical consequences of differential growth in epithelia. Typically, differential growth in mosaics leads to cell crowding and compaction in the vicinity of the faster-growing genotype [23,30*]. …”