Linking YAP to Müller Glia Quiescence Exit in the Degenerative Retina

Abstract

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 TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar

“…However, it is unclear how chronic MC reactivity in mammals exacerbates injury response leading to glial scar formation. Another important feature of MC reactivity is their exit from quiescence in response to injury [31]. We evaluate MC-cycle reentry using PCNA in both animal models ( Fig.…”

Awakening the regenerative potential of the mammalian retina

“…Recent studies from our labs, and the lab of Dr Muriel Perron, have identified the Hippo pathway as an essential molecular mechanism that blocks mammalian MG cell cycle entry and reprogramming to a progenitor-like cellular state (Hamon et al, 2019;Rueda et al, 2019). Here, we highlight these data and discuss the advantages of developing additional strategies to unlock the endogenous regenerative potential of the mammalian retina.…”

“…For almost two decades, the molecular mechanism suppressing sustained cyclin D3 expression and blocking MG proliferation remained unknown. Recently, we and the lab of Dr Muriel Perron identified signaling by the Hippo pathway as an essential molecular block to sustained MG proliferation and reprogramming to a progenitor-like state (Hamon et al, 2019;Rueda et al, 2019) (Fig. 2).…”

“…Studies of zebrafish retinal regeneration will likely continue to shed light on additional requirements, some of which will likely crosstalk with the Hippo pathway, that may then be applied to the mouse. Candidates for such factors include the PI3K-AKT-mTOR, JAK-STAT and MAPK-ERK pathways, as well as EGF signaling (Hamon et al, 2019;Rueda et al, 2019;Wan and Goldman, 2016). It will also be interesting to determine whether differential regulation of yap1 occurs in zebrafish MG compared to mice.…”

“…As researchers begin to delve deeper into YAP-and/or β-cateninmediated mouse MG reprogramming (Hamon et al, 2019;Rueda et al, 2019;Yao et al, 2016Yao et al, , 2018, we recommend that it would be wise to remember the decade-long misinterpretation of retinal cell transplantations as a cautionary tale (Nickerson et al, 2018). Irrespective of whether the Hippo or Wnt pathways are being targeted, any strategy aimed at awakening the regenerative potential of resident MG comes with a specific set of practical matters and technical issues that we must address.…”