Linking YAP to Muller Glia Quiescence Exit in the Degenerative Retina

Contrasting with fish or amphibian, retinal regeneration from Muller 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 Muller cells following retinal injury. Conditional Yap deletion in mouse Muller 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 Muller 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 Muller cell proliferative response to injury and highlight a YAP-EGFR (epidermal growth factor receptor) axis by which Muller cells exit their quiescence state, a critical step toward regeneration.