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other·ophthalmology, glaucoma, retina, ocular immunology, animal science·PMC10811226

Uveitic glaucoma-like features in Yap conditional knockout mice

Cell Death Discovery · 11 authors, 4 centres

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TL;DR

This study demonstrates that conditional knockout of Yap in Müller glia and ciliary body non-pigmented epithelium in mice leads to progressive uveitic glaucoma-like features, including ciliary body collapse, blood-aqueous barrier breakdown, retinal vascular defects, reactive gliosis, glutamate recycling impairment, and retinal ganglion cell loss. The findings suggest YAP dysfunction may contribute to glaucoma pathogenesis in humans and provide a new preclinical model for uveitic glaucoma.

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**Background:** Glaucoma is a multifactorial optic neuropathy with limited animal models. YAP, a Hippo pathway effector, is expressed in ocular cells affected in glaucoma (ciliary body non-pigmented epithelium, trabecular meshwork, Müller glia) and has been linked to primary open-angle glaucoma risk. The role of YAP in ciliary body and Müller cell function in glaucoma development was unknown.

**Methods:** The authors used Yap flox/flox;Rax-CreERT2 mice (Yap cKO) to delete Yap in Müller glia and ciliary body non-pigmented epithelium at postnatal day 10. They assessed ciliary body morphology, blood-aqueous barrier integrity (albumin staining, fluorescein angiography), intraocular pressure (rebound tonometry), retinal ganglion cell survival (Brn3a, RBPMS immunostaining), optic nerve head morphology (OCT), neurofilament light chain expression, gliosis (GFAP), glutamate/glutamine ratio (LC-HRMS), and expression of glutamate recycling proteins (GS, Kir4.1, AQP4) by immunostaining and western blot. Whole transcriptome analysis (RNA-seq) was performed on 2-month-old retinas.

**Key Results:** Yap cKO mice showed progressive ciliary body collapse (100% by 6-9 months), phenocopying human uveitic patients. Blood-aqueous barrier breakdown was evident from 2 months. Intraocular pressure was significantly elevated only in females at 9 months (p ≤ 0.05). Retinal ganglion cell loss was observed at 9 months (27% decrease, p ≤ 0.01) and 12 months (30% decrease, p ≤ 0.0001) by Brn3a staining, confirmed by RBPMS at 9 months (p ≤ 0.05). Optic nerve head excavation was present from 2 months. Reactive gliosis (GFAP upregulation) started at 6 months. Glutamate/glutamine ratio was significantly increased at 9 months (p ≤ 0.05), with decreased glutamine content (p ≤ 0.001). Glutamine synthetase was downregulated from 2 months (p ≤ 0.01), and Kir4.1 and AQP4 were decreased at 9 months (p ≤ 0.01). RNA-seq identified 276 differentially expressed genes at 2 months, with enrichment in extracellular matrix organization, blood vessel morphogenesis, and glutamatergic synaptic transmission. Fibronectin-1 (Fn1) was the most significant hub gene.

**Clinical Implications:** This study provides the first experimental evidence that YAP dysfunction in Müller glia and ciliary body can trigger uveitic glaucoma-like pathology. The Yap cKO mouse model recapitulates key features of human uveitic glaucoma, including ciliary body degeneration, blood-aqueous barrier breakdown, and progressive retinal ganglion cell loss. It offers a valuable tool to study mechanisms linking anterior uveitis to glaucoma and to test therapeutic strategies targeting YAP-related pathways.

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other

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ophthalmology

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ORIGINAL PAPER

PMC10811226

Uveitic glaucoma-like features in Yap conditional knockout mice

Cell Death Discovery

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ABSTRACT

Abstract Glaucoma is a multifactorial neurodegenerative disease characterized by the progressive and irreversible degeneration of the optic nerve and retinal ganglion cells. Despite medical advances aiming at slowing degeneration, around 40% of treated glaucomatous patients will undergo vision loss. It is thus of utmost importance to have a better understanding of the disease and to investigate more deeply its early causes. The transcriptional coactivator YAP, an important regulator of eye homeostasis, has recently drawn attention in the glaucoma research field. Here we show that Yap conditional knockout mice ( Yap cKO), in which the deletion of Yap is induced in both Müller glia (i.e. the only retinal YAP-expressing cells) and the non-pigmented epithelial cells of the ciliary body, exhibit a breakdown of the aqueous-blood barrier, accompanied by a progressive collapse of the ciliary body. A similar phenotype is observed in human samples that we obtained from patients presenting with uveitis. In addition, aged Yap cKO mice harbor glaucoma-like features, including deregulation of key homeostatic Müller-derived proteins, retinal vascular defects, optic nerve degeneration and retinal ganglion cell death. Finally, transcriptomic analysis of Yap cKO retinas pointed to early-deregulated genes involved in extracellular matrix organization potentially underlying the onset and/or progression of the observed phenotype. Together, our findings reveal the essential role of YAP in preserving the integrity of the ciliary body and retinal ganglion cells, thereby preventing the onset of uveitic glaucoma-like features. Subject terms: Cell death in the nervous system, Glial biology, Neurodegeneration

CITATION EXPORT

Juliette Bitard, Elodie-Kim Grellier, Sophie Lourdel et al.. Uveitic glaucoma-like features in Yap conditional knockout mice. Cell Death Discovery. (2024). https://doi.org/10.1038/s41420-023-01791-6

AUTHORS

11 · 4 CENTRES

Juliette Bitard, Elodie-Kim Grellier, Sophie Lourdel, Helena Prior Filipe, Annaïg Hamon, François Fenaille, Florence Anne Castelli, Emeline Chu-Van, Jérôme E Roger, Morgane Locker, Muriel Perron

1Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, Saclay, France
2West Lisbon Hospitals Center, Hospital de Egas Moniz, Lisbon, Portugal
3Egas Moniz Center for Interdisciplinary Research, Lisbon, Portugal
4Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, Gif sur Yvette, France