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

Abstract

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