The Hippo pathway, best known for its role in growth control, has been implicated in tissue repair and regeneration in various contexts. In this issue, two papers provide insights into how Hippo signalling regulates tissue growth during regeneration.
In the first report (p. 2740), Joy Meserve and Robert Duronio study the Drosophila eye to investigate the mechanisms that allow quiescent cells to re-enter the cell cycle and proliferate in response to tissue damage. Using an RNAi screen, they reveal that scalloped (sd), which encodes a transcriptional effector of the Hippo pathway, is required for compensatory proliferation following tissue damage. They demonstrate that Sd and its binding partner Yorkie (Yki) are required to induce Cyclin E expression and hence drive S-phase entry in regenerating eye discs. The researchers further show that Ajuba (Jub), an upstream regulator of Hippo signalling, is needed for cell cycle re-entry. Given the roles of Jub in sensing epithelial integrity, the authors propose that the apoptotic force induced by tissue damage in this context triggers Jub and Sd/Yki activation that, in turn, allows for compensatory proliferation and tissue repair.
In a second paper, Antonio Jacinto and colleagues reveal a role for the Hippo pathway effector Yap in zebrafish fin regeneration (p. 2752). Fin regeneration involves three steps – wound healing, blastema formation and tissue outgrowth – and the researchers show that Yap activation (and hence nuclear localisation) is dynamic during these steps. Yap is nuclear during wound healing, remains nuclear during blastema formation, and then is cytoplasmic in regions distal to the wound but nuclear in proximal regions during outgrowth. They further show, by modulating Yap levels, that Yap regulates cell proliferation and the expression of key regeneration factors. The researchers also report that Yap localisation correlates with changes in cell density and cell morphology along the blastema proximal-distal axis. Finally, they observe similar gradients in α-catenin and F-actin localisation, suggesting a model in which a mechanotransduction process involving changes in cell morphology, junctional assembly and the cytoskeleton controls the activation of Yap to regulate tissue regeneration.