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 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 TAZdependent 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.

Late-onset glaucoma in Yap conditional knockout mouse

“…GS levels in Müller cells were significantly decreased from two months onwards in Yap cKO retinas compared to control ones (Figure 6). Consistently with previous data we published 9 , this was followed in older animals by the downregulation of two other proteins involved in glutamate recycling, namely the inwardly rectifying potassium channel (Kir4.1) 7 and the water channel Aquaporin-4 (AQP4) 28,29 (Figure 6). Of note, although Kir4.1 was downregulated in Müller cell processes, its expression was increased at their endfeet within the ganglion cell layer.…”

“…YAP is now recognized as a crucial mediator of eye development, homeostasis and disease 9,30,31 . Beside its major functions as a cell-autonomous regulator of key cellular processes (proliferation, differentiation, apoptosis…), YAP also acts at the level of the tissue structure 32 by bridging extracellular matrix changes to the cell through its mechanosensory activity, and by contributing to the establishment and maintenance of cellular junctions within epithelia 33 .…”

“…Despite major breakthroughs in the global understanding of glaucoma, new animal models are still needed to further dissect the complex etiology of this group of diseases. The Hippo pathway effector YAP recently emerged as an orchestrator of eye homeostasis 8 and we showed in particular that its haploinsufficiency in 12-month-old mice results in photoreceptor degeneration 9 . With regards to the glaucoma research field, a genome wide association study identified Yap as a new risk locus for primary open-angle glaucoma 10 .…”

The Molecular Network of YAP/Yorkie at the Cell Cortex and their Role in Ocular Morphogenesis

“…In addition, recent findings on Yap haploinsufficiency indicate Müller glia dysfunction, late-onset cone degeneration, and reduced cone-mediated visual response [57]. Finally, YAP deficient endothelial cells show damaged retinal vascularisation and obstructive astrocyte network formation and maturation [58].…”

Specific ablation of Hippo signalling component Yap1 in retinal progenitors and Müller cells results in late onset retinal degeneration

“…He et al, 2019; Holt et al, 2017; Miesfeld et al, 2015; Raghunathan et al, 2014; Williamson et al, 2014). Recent work indicated that retinas in Yap1 heterozygous mice exhibited altered Müller cell homeostatic function, and causing late‐onset cone degeneration (Masson et al, 2020). Although these data suggest YAP function in Müller cells for the preservation of cone integrity, the specific requirement for YAP in in other components of retina has not been fully explored.…”