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.

Contrasting with fish or amphibian, retinal regeneration from Müller glial cells is largely limited in mammals. In our quest towards the identification of molecular cues that may boost their stemness potential, we investigated the involvement of the Hippo pathway effector YAP, which we previously found to be upregulated in Müller cells following retinal injury. We report that conditional Yap deletion in Müller cells prevents the upregulation of cell cycle genes that normally accompanies reactive gliosis upon photoreceptor cell death. This occurs as a consequence of defective EGFR signaling. Consistent with a function of YAP in triggering Müller glia cell cycle re-entry, we further show that in Xenopus, a species endowed with efficient regenerative capacity, YAP is required for their injurydependent proliferative response. Finally, and noteworthy, we reveal that YAP overactivation in mouse Müller cells is sufficient to induce their reprogramming into highly proliferative cells. Overall, we unravel a pivotal role for YAP in tuning Müller cell response to injury and highlight a novel YAP-EGFR axis by which Müller cells exit their quiescence state, a critical step towards regeneration. Key words: Müller cells, reactive gliosis, retinal regeneration, Hippo/YAP pathway, EGFRpathway Neurodegenerative retinal diseases, such as retinitis pigmentosa or age-related macular degeneration, ultimately lead to vision loss, as a consequence of photoreceptor cell death. Driving retinal self-repair from endogenous neural stem cells in patients represents an attractive therapeutic strategy. Among cellular sources of interest are Müller cells, the major glial cell type in the retina. These cells are essential for maintaining retinal homeostasis 1 but also proved their potential for endogenous regeneration. In certain species, such as zebrafish or Xenopus, they behave as genuine stem cells, endowed with the ability to reprogram into a progenitor-like state upon retinal damage, proliferate and regenerate lost photoreceptors 2-4 . In mammals, however, their proliferative response to injury is extremely limited. Following acute retinal damage, mouse Müller glial cells rapidly re-enter G1-phase of the cell cycle, as inferred by increased cyclin gene expression, but they rarely divide 5 . Suggesting that they nonetheless retain remnants of repair capacities, their proliferation and neurogenic potential can be stimulated, for instance by supplying exogenous growth factors such as Heparin-binding EGF-like growth factor (HB-EGF), or by overexpressing the proneural gene Ascl1a 3,6-8 . Our understanding of the genetic/signaling network sustaining Müller cell stemness potential is however far from being complete. Identifying novel molecular cues is thus of utmost importance to foresee putative candidates that could be targeted for regenerative medicine. We here investigated whether the Hippo pathway effector YAP might influence Müller cell reactivation and how it would intersect with other critical signaling pathways. The Hippo pathway is a kina...