Mice Deficient in TAZ (Wwtr1) Demonstrate Clinical Features of Late-Onset Fuchs’ Endothelial Corneal Dystrophy

Abstract

Purpose We sought to define the role of Wwtr1 in murine ocular structure and function and determine the role of mechanotransduction in Fuchs’ endothelial corneal dystrophy (FECD), with emphasis on interactions between corneal endothelial cells (CEnCs) and Descemet's membrane (DM). Methods A Wwtr1 deficient mouse colony was established, and advanced ocular imaging, atomic force microscope (AFM), and histology/immunofluorescence were performed. Corneal endothelial wound healing was assessed using cryoinjury and phototherapeutic keratectomy in Wwtr1 deficient mice. Expression of WWTR1 /TAZ was determined in the corneal endothelium from normal and FECD-affected patients; WWTR1 was screened for coding sequence variants in this FECD cohort. Results Mice deficient in Wwtr1 had reduced CEnC density, abnormal CEnC morphology, softer DM, and thinner corneas versus wildtype controls by 2 months of age. Additionally, CEnCs had altered expression and localization of Na/K-ATPase and ZO-1. Further, Wwtr1 deficient mice had impaired CEnC wound healing. The WWTR1 transcript was highly expressed in healthy human CEnCs comparable to other genes implicated in FECD pathogenesis. Although WWTR1 mRNA expression was comparable between healthy and FECD-affected patients, WWTR1/TAZ protein concentrations were higher and localized to the nucleus surrounding guttae. No genetic associations were found in WWTR1 and FECD in a patient cohort compared to controls. Conclusions There are common phenotypic abnormalities seen between Wwtr1 deficient and FECD-affected patients, suggesting that Wwtr1 deficient mice could function as a murine model of late-onset FECD. Despite the lack of a genetic association between FECD and WWTR1 , aberrant WWTR1 /TAZ protein subcellular localization and degradation may play critical roles in the pathogenesis of FECD.

Characterization of a novel mouse model for Fuchs Endothelial Corneal Dystrophy

“…This mouse model presented decreased corneal endothelial cell numbers, shape changes, and a softer Descemet’s Membrane, among the characteristic features of FECD. This study reveals the role of YAP/TAZ signaling in corneal endothelial homeostasis 66 . However, corneal thinning and the absence of guttae in the Wwrt1 -/- animal model indicate that the YAP/TAZ pathways may not alone be responsible for the FECD disease phenotypes.…”

“…Polymegathism is a characteristic feature of FECD 12,13 . To identify whether the loss of YAP/TAZ pathways would result in corneal endothelial dysfunctions, Thomasy and colleagues used a knockout mouse model of Wwrt1 , a primary YAP/TAZ pathway transducer 66 . This mouse model presented decreased corneal endothelial cell numbers, shape changes, and a softer Descemet’s Membrane, among the characteristic features of FECD.…”

Unlocking the therapeutic potential of the corneal endothelium: Intravital imaging reveals endogenous regenerative capabilities

“…In contrast to large animal models, the mouse is readily amenable to genetic manipulation. Furthermore, mouse knockout models of loci associated with Fuchs’ endothelial corneal dystrophy show clinical features of the disease [16, 17]. We therefore sought to capitalize on contemporary genetic tools to investigate different facets of corneal endothelial physiology, by live imaging.…”