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 Müller glia. We first discovered an unexpected tempora...

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Bibliographic Details
Published in:Cell death & disease 2020-08, Vol.11 (8), p.631, Article 631
Main Authors: Masson, Christel, García-García, Diana, Bitard, Juliette, Grellier, Élodie-Kim, Roger, Jérôme E, Perron, Muriel
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Animals
Animals, Newborn
Carrier Proteins - metabolism
Cell Cycle
Cell Cycle Proteins - metabolism
Cell Proliferation
Cone Dystrophy - genetics
Cone Dystrophy - pathology
Degeneration
Dosage compensation
Dystrophy
Embryogenesis
Ependymoglial Cells - metabolism
Ependymoglial Cells - pathology
Epidermal growth factor receptors
ErbB Receptors - metabolism
Gene Deletion
Gene Expression Regulation
Haploinsufficiency
Haploinsufficiency - genetics
Homeostasis
Life Sciences
Mice, Knockout
Models, Biological
Neural stem cells
Neuronal-glial interactions
Opsins
Opsins - metabolism
Phenotype
Phenotypes
Potentiation
Preservation
Retina
Retina - pathology
Retinal Cone Photoreceptor Cells - metabolism
Retinal Cone Photoreceptor Cells - pathology
Retinal Degeneration - genetics
Retinal Degeneration - pathology
Stem Cells - metabolism
Trans-Activators - metabolism
Yes-associated protein
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-020-02860-9