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

Safiah Mohamed Ali; Bhav Harshad Parikh; Queenie Shu Woon Tan; Barbara Hübner; Aleksandra N Kozyrina; Animesh Banerjee; Jie Zhao; Debbie Goh; Hanumakumar Bogireddi; Sia Wey Yeo; Daniel Soo Lin Wong; Jianliang Xu; Kim Chi Tran; Zengping Liu; Yun-Zheng Le; Veluchamy Amutha Barathi; Kang Hao Cheong; Jacopo Di Russo; Alexander Ludwig; Walter Hunziker; Xinyi Su

doi:10.1016/j.isci.2025.113673

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

iScience. 2025 Oct 3;28(11):113673. doi: 10.1016/j.isci.2025.113673. eCollection 2025 Nov 21.

Authors

Safiah Mohamed Ali¹, Bhav Harshad Parikh^{1

2}, Queenie Shu Woon Tan¹, Barbara Hübner^{3

4}, Aleksandra N Kozyrina^{5

6}, Animesh Banerjee¹, Jie Zhao^{7

8}, Debbie Goh², Hanumakumar Bogireddi^{1

2}, Sia Wey Yeo⁹, Daniel Soo Lin Wong^{1

2}, Jianliang Xu¹, Kim Chi Tran^{1

2}, Zengping Liu^{1

2

9

10}, Yun-Zheng Le¹¹, Veluchamy Amutha Barathi^{2

9

12}, Kang Hao Cheong^{7

13}, Jacopo Di Russo^{5

6

14}, Alexander Ludwig^{3

4}, Walter Hunziker^{1

15}, Xinyi Su^{1

2

9

16

10}

Affiliations

¹ Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore 138673, Singapore.
² Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore 119228, Singapore.
³ School of Biological Sciences, Nanyang Technological University (NTU), Singapore 637551, Singapore.
⁴ NTU Institute of Structural Biology, Nanyang Technological University (NTU), Singapore 636921, Singapore.
⁵ Interdisciplinary Centre for Clinical Research, RWTH Aachen University, 52074 Aachen, Germany.
⁶ Institute of Molecular and Cellular Anatomy, RWTH Aachen University, 52074 Aachen, Germany.
⁷ Division of Mathematical Sciences, School of Physical and Mathematical Sciences, Nanyang Technological University (NTU), Singapore 637371, Singapore.
⁸ Science, Mathematics and Technology, Singapore University of Technology and Design (SUTD), Singapore 487372, Singapore.
⁹ Singapore Eye Research Institute (SERI), Singapore 169856, Singapore.
¹⁰ Centre for Innovation and Precision Eye Health, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore 119228, Singapore.
¹¹ Department of Medicine, Cell Biology, and Ophthalmology and Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City OK 73104, USA.
¹² Academic Clinical Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore.
¹³ College of Computing and Data Science, Nanyang Technological University (NTU), Singapore 639798, Singapore.
¹⁴ DWI - Leibniz-Institute for Interactive Materials, 52074 Aachen, Germany.
¹⁵ Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore 117593, Singapore.
¹⁶ Department of Ophthalmology, National University Hospital (NUH), Singapore 119228, Singapore.

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.

Keywords: Cell biology; Model organism.