Linking YAP to Müller Glia Quiescence Exit in the Degenerative Retina

Abstract

Contrasting 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.