RAD21 deficiency drives corneal to scleral differentiation fate switching via upregulating WNT9B

Hongyan Liu; Benxiang Qi; Guanghui Liu; Haoyun Duan; Zongyi Li; Zhaoying Shi; Yonglong Chen; Wai Kit Chu; Qingjun Zhou; Bi Ning Zhang

doi:10.1016/j.isci.2024.109875

RAD21 deficiency drives corneal to scleral differentiation fate switching via upregulating WNT9B

iScience. 2024 May 3;27(6):109875. doi: 10.1016/j.isci.2024.109875. eCollection 2024 Jun 21.

Authors

Hongyan Liu^{1

2

3}, Benxiang Qi^{2

3

4}, Guanghui Liu⁵, Haoyun Duan^{2

3

4}, Zongyi Li^{2

3

4}, Zhaoying Shi⁵, Yonglong Chen⁵, Wai Kit Chu⁶, Qingjun Zhou^{2

3

4}, Bi Ning Zhang^{2

3

4}

Affiliations

¹ Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
² Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.
³ School of Ophthalmology, Shandong First Medical University, Qingdao, China.
⁴ State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, China.
⁵ Department of Chemical Biology, School of Life Sciences, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, China.
⁶ Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Abstract

The cornea and sclera are distinct adjacent tissues, yet their stromal cells originate from common neural crest cells (NCCs). Sclerocornea is a disease characterized by an indistinguishable boundary between the cornea and sclera. Previously, we identified a RAD21 mutation in a sclerocornea pedigree. Here, we investigated the impacts of RAD21 on NCC activities during eye development. RAD21 deficiency caused upregulation of PCDHGC3. Both RAD21 knockdown and PCDHGC3 upregulation disrupted the migration of NCCs. Transcriptome analysis indicated that WNT9B had 190.9-fold higher expression in scleral stroma than in corneal stroma. WNT9B was also significantly upregulated by both RAD21 knockdown and PCDHGC3 overexpression, and knock down of WNT9B rescued the differentiation and migration of NCCs with RAD21 deficiency. Consistently, overexpressing wnt9b in Xenopus tropicalis led to ocular developmental abnormalities. In summary, WNT9B is a determinant factor during NCC differentiation into corneal keratocytes or scleral stromal cells and is affected by RAD21 expression.

Keywords: Cell biology; Developmental biology.