ZO-1/Tjp1 and ZO-2/Tjp2 deletion in retinal pigment epithelium causes progressive retinal degeneration
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.
Authors
- Animesh Banerjee (ORCID: https://orcid.org/0000-0003-0820-4377)
- Kang Hao Cheong (ORCID: https://orcid.org/0000-0002-4475-5451)
- Barbara Hübner (ORCID: https://orcid.org/0000-0001-5148-0823)
- Hanumakumar Bogireddi
- Daniel Soo Lin Wong (ORCID: https://orcid.org/0000-0001-7425-6736)
- Veluchamy A. Barathi (ORCID: https://orcid.org/0000-0002-6477-9784)
- Safiah Mohamed Ali (ORCID: https://orcid.org/0000-0003-1821-2581)
- Aleksandra N. Kozyrina (ORCID: https://orcid.org/0000-0003-1369-9386)
- Jacopo Di Russo (ORCID: https://orcid.org/0000-0001-6731-9612)
- Walter Hunziker (ORCID: https://orcid.org/0000-0002-5265-4933)
- Alexander Ludwig (ORCID: https://orcid.org/0000-0002-0696-5298)
- Zengping Liu (ORCID: https://orcid.org/0000-0002-2578-293X)
- Queenie Shu Woon Tan
- Bhav Harshad Parikh (ORCID: https://orcid.org/0000-0003-3835-8887)
- Jianliang Xu (ORCID: https://orcid.org/0000-0002-2277-2197)
- Sia Wey Yeo
- Xinyi Su (ORCID: https://orcid.org/0000-0002-1480-6713)
- Debbie Goh (ORCID: https://orcid.org/0000-0002-2510-3503)
- Kim Peng Tan (ORCID: https://orcid.org/0009-0004-8898-7459)
- Jie Zhao (ORCID: https://orcid.org/0009-0006-5391-107X)
- Yun-Zheng Le
Institutions
- Agency for Science, Technology and Research (SG)
- Singapore University of Technology and Design (SG)
- National University of Singapore (SG)
- Nanyang Technological University (SG)
- Singapore National Eye Center (SG)
- DWI – Leibniz Institute for Interactive Materials (DE)
- Singapore Eye Research Institute (SG)
- Duke-NUS Medical School (SG)
- National University Hospital (SG)
- University of Oklahoma Health Sciences Center (US)
- Institute of Molecular and Cell Biology (SG)
- RWTH Aachen University (DE)
Publication Details
- Journal
- iScience
- Published
- 2025-10-04
- DOI
- https://doi.org/10.1016/j.isci.2025.113673
- Primary Topic
- Retinal Development and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00