YAP protects the eye from uveitic glaucoma by preserving retinal and anterior chamber homeostases

Abstract

Purpose : The role of the transcription coactivator YAP has been studied during eye development but its implication in ocular homeostasis and diseases is much less documented. YAP is expressed by several ocular cell types including the non-pigmented cells of the ciliary body (CB) as well as Müller glial cells (MGs) of the neuroretina. Here, we assessed whether postnatal Yap deletion in these two cell types could affect eye homeostasis during aging.

Methods : Specific Yap deletion in CB and MGs was induced in a conditional mouse model (Yap cKO) at P10. The phenotype was investigated by western-blot, immunohistochemistry, and RNA-sequencing (RNA-seq). Blood defects were identified by fluorescein angiography. Optic nerve degeneration was assessed by optical coherence tomography. Intraocular pressure (IOP) was recorded by a rebound tonometer. Imaging of the CB in healthy and uveitic human patients was performed by ultrasound biomicroscopy.

Results : At two months, Yap cKO eyes exhibited distended ciliary processes and blood leakage from the iris. Anterior uveitis became chronic with age resulting in collapse of the CB as observed in human patients. At nine months, the CB was dysfunctional as inferred by pathway analysis of RNA-seq data showing deregulation of genes belonging to the GO group “symporter activity” that encode regulators of aqueous humor composition. In line with this, IOP was increased in aged female mice whereas males had a trend towards hypotony. Since such a phenotype is highly reminiscent of glaucoma, we assessed whether Yap cKO mice exhibited other hallmarks of the disease, focusing on the neuroretina. At two months, MGs–derived glutamine synthetase – the key enzyme in the regulation of glutamate metabolism – was downregulated. By six months of age, MGs gliosis and microglial cell activation were evident. Finally, nine–month–old Yap cKO retinas harbored signs of blood defects, disturbed glutamate metabolism, reduced number of retinal ganglion cells, and excavation of the optic nerve head.

Conclusions : Altogether, these results show that Yap deletion in both the CB and MGs causes chronic anterior uveitis followed by secondary glaucoma. This highlights a novel and unsuspected function of YAP in homeostasis maintenance of both the neuroretina and the anterior chamber which may open new avenues towards a better understanding of glaucoma etiology.

This is a 2021 ARVO Annual Meeting abstract.