Graphical Abstract Highlights d YAP is required for Xenopus M€ uller glia proliferation in response to injury d YAP is required for mouse M€ uller glia exit from quiescence upon degeneration d YAP5SA reprograms mouse M€ uller glia into highly proliferative cells d YAP functionally interacts with EGFR signaling in M€ uller cells (M.P.) In BriefWhile fish and amphibian M€ uller cells behave as retinal stem cells upon injury, their regenerative potential is limited in mammals. Hamon et al. show that YAP is required for their cell-cycle re-entry in Xenopus and is sufficient in mouse to awake them from quiescence and trigger their proliferative response. SUMMARYContrasting with fish or amphibian, retinal regeneration from M€ uller glia is largely limited in mammals. In our quest toward the identification of molecular cues that may boost their stemness potential, we investigated the involvement of the Hippo pathway effector YAP (Yes-associated protein), which is upregulated in M€ uller cells following retinal injury. Conditional Yap deletion in mouse M€ uller cells prevents cell-cycle gene upregulation that normally accompanies reactive gliosis upon photoreceptor cell death. We further show that, in Xenopus, a species endowed with efficient regenerative capacity, YAP is required for their injury-dependent proliferative response. In the mouse retina, where M€ uller cells do not spontaneously proliferate, YAP overactivation is sufficient to induce their reprogramming into highly proliferative cells. Overall, we unravel a pivotal role for YAP in tuning M€ uller cell proliferative response to injury and highlight a YAP-EGFR (epidermal growth factor receptor) axis by which M€ uller cells exit their quiescence state, a critical step toward regeneration.

The adult frog retina retains a reservoir of active neural stem cells that contribute to continuous eye growth throughout life. We found that Yap, a downstream effector of the Hippo pathway, is specifically expressed in these stem cells. Yap knock-down leads to an accelerated S-phase and an abnormal progression of DNA replication, a phenotype likely mediated by upregulation of c-Myc. This is associated with an increased occurrence of DNA damage and eventually p53-p21 pathway-mediated cell death. Finally, we identified PKNOX1, a transcription factor involved in the maintenance of genomic stability, as a functional and physical interactant of YAP. Altogether, we propose that YAP is required in adult retinal stem cells to regulate the temporal firing of replication origins and quality control of replicated DNA. Our data reinforce the view that specific mechanisms dedicated to S-phase control are at work in stem cells to protect them from genomic instability.DOI: http://dx.doi.org/10.7554/eLife.08488.001