Bitard, J. | Search bioRxiv

bioRxiv2020

Yap haploinsufficiency leads to Müller cell dysfunction and late-onset cone dystrophy

Hippo signalling regulates eye growth during embryogenesis through its effectors YAP and TAZ. Taking advantage of a Yap heterozygous mouse line, we here sought to examine its function in adult neural retina, where YAP expression is restricted to Muller glia. We first discovered an unexpected temporal dynamic of gene compensation. At post-natal stages, Taz upregulation occurs, leading to a gain of function-like phenotype characterized by EGFR signalling potentiation and delayed cell cycle exit of retinal progenitors. In contrast, Yap+/- adult retinas no longer exhibit TAZ-dependent dosage compensation. In this context, Yap haploinsufficiency in aged individuals results in Muller glia dysfunction, late-onset cone degeneration and reduced cone-mediated visual response. Alteration of glial homeostasis and altered patterns of cone opsins were also observed in Muller cell specific conditional Yap knockout mice. Together, this study highlights a novel YAP function in Muller cells for the maintenance of retinal tissue homeostasis and the preservation of cone integrity. It also suggests that YAP haploinsufficiency should be considered and explored as a cause of cone dystrophies in human. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/953943v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@166de41org.highwire.dtl.DTLVardef@898b74org.highwire.dtl.DTLVardef@22ad92org.highwire.dtl.DTLVardef@b189dc_HPS_FORMAT_FIGEXP M_FIG C_FIG Main Points O_LIThis study finds unsuspected dynamics of YAP compensatory mechanisms in the retina of Yap+/- mice C_LIO_LIYap haploinsufficiency results in Muller glia dysfunction in aged mice, leading to late-onset cone dystrophy C_LI

neuroscience↗

bioRxiv2018

Linking YAP to Müller glia quiescence exit in the degenerative retina

Contrasting with fish or amphibian, retinal regeneration from Muller 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 Muller cells following retinal injury. We report that conditional Yap deletion in Muller 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 Muller glia cell cycle re-entry, we further show that in Xenopus, a species endowed with efficient regenerative capacity, YAP is required for their injury-dependent proliferative response. Finally, and noteworthy, we reveal that YAP overactivation in mouse Muller cells is sufficient to induce their reprogramming into highly proliferative cells. Overall, we unravel a pivotal role for YAP in tuning Muller cell response to injury and highlight a novel YAP-EGFR axis by which Muller cells exit their quiescence state, a critical step towards regeneration.

developmental biology↗