# ZO-1/Tjp1 and ZO-2/Tjp2 deletion in retinal pigment epithelium causes progressive retinal degeneration

## TL;DR

Deleting ZO-1 and ZO-2 in retinal pigment epithelium leads to retinal degeneration and impaired wound healing.

## Contribution

This study reveals the essential role of ZO-1/2 in maintaining retinal integrity and wound healing in mice.

## Key findings

- ZO-1/2 double knockout causes retinal pigment epithelium dysfunction and retinal thinning.
- DKO RPE cells show increased YAP activity and cell cycle re-entry.
- Laser-induced damage in DKO mice leads to poor wound healing and persistent hyper-proliferation.

## Abstract

Tight junction protein-1 and -2 (Tjp1/ZO-1 and Tjp2/ZO-2) function as scaffold proteins within the tight junction complexes of the blood-retinal barrier (BRB). Although the breakdown of the BRB is implicated in retinopathies, the contribution of ZO-1/2 in the pathogenesis of retinopathies is unknown. To understand their role, we generated RPE-specific conditional ZO-1/2 single KOs (T1KO/T2KO) and ZO-1/2 double knockout (DKO) mice. While T1KO and T2KO did not exhibit overt retinal phenotypes, DKO demonstrated a strong retinal phenotype from 1-month post-KO induction. This includes the loss of RPE integrity and retinal thinning. Furthermore, RPE in DKO re-entered the cell cycle with upregulated YAP. At 12 months, we observed severe structural and functional retinal deterioration. In response to laser-induced damage, RPE displayed persistent hyper-proliferation, delayed wound repair, and the up-regulation of YAP. These studies confirmed the critical role of ZO-1/2 in maintaining an intact BRB and revealed a role of ZO-1/2 in wound healing.

•Tjp1-2 double KO (DKO) disrupts RPE structure and function•DKO RPE shows YAP upregulation and re-entry into the cell cycle•DKO mice exhibit impaired wound healing after laser-induced damage•DKO mice show progressive structural and functional retinal deterioration

Tjp1-2 double KO (DKO) disrupts RPE structure and function

DKO RPE shows YAP upregulation and re-entry into the cell cycle

DKO mice exhibit impaired wound healing after laser-induced damage

DKO mice show progressive structural and functional retinal deterioration

Cell biology; Model organism