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 Müller glia. We first discovered an unexpected temporal dynamic of gene compensation. At postnatal stages, Taz upregulation occurs, leading to a gain of function-like phenotype characterised 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 Müller 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 Müller cell-specific conditional Yap-knockout aged mice. Together, this study highlights a novel YAP function in Müller 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.
Highlights
Deregulation of key signalling pathways, such as Wnt orNotch, well known for their involvement in retinal development, are at the origin of retinal diseases in adults[1,2]
Consistent with the known critical role of the Hippo pathway in regulating neural progenitor cell proliferation[19], we found that such enhanced TAZ activity in Yap+/− postnatal retinas is associated with a gain of function-like phenotype, i.e., delayed cell-cycle exit of retinal progenitors
By immuno-histochemical (IHC) analysis, we found that YAP expression was strongly diminished in both Müller glial and retinal pigment epithelium (RPE) cells, where YAP has previously been shown to be expressed[17] (Fig. 1c)
Summary
Deregulation of key signalling pathways, such as Wnt or. Well known for their involvement in retinal development, are at the origin of retinal diseases in adults[1,2]. Studying developmental signalling pathways can allow the identification of possible causes of retinal disorders in adults, pinpointing possible targets for therapeutic approaches. The Hippo signalling tightly regulates eye development, and its deregulation in animal models leads to severe ocular defects (reviewed in[3,4]). This signalling pathway consists of a kinase cascade that phosphorylates the transcription coactivators YAP (Yes associated protein) and TAZ (WW domain-containing transcription regulator 1), causing their retention in the cytoplasm or their degradation. We found that depletion of one Yap allele leads to a transient TAZ
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