Progressive corneal endothelial disease eventually leads to corneal edema and vision loss due to the limited regenerative capacity of the corneal endothelium in vivo and is a major indication for corneal transplantation. Despite the relatively high success rate of corneal transplantation, there remains a pressing global clinical need to identify improved therapeutic strategies to address this debilitating condition. To evaluate the safety and efficacy of novel therapeutics, there is a growing demand for pre-clinical animal models of corneal endothelial dysfunction. In this review, experimentally induced, spontaneously occurring and genetically modified animal models of corneal endothelial dysfunction are described to assist researchers in making informed decisions regarding the selection of the most appropriate animal models to meet their research goals.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.