ArticleInvestigative ophthalmology & visual science2025
Heterozygous Tcf4 Deficiency Mitigates Fuchs Endothelial Corneal Dystrophy Progression in a Mouse Model.
Article in Investigative ophthalmology & visual science, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Purpose: The purpose of this study was to use Col8a2Q455K/Q455K mice, an established Fuchs endothelial corneal dystrophy (FECD) model, to investigate whether heterozygous knockout of Tcf4 expression could ameliorate the progression of FECD. Methods: Tcf4 heterozygous knockout mice were generated using CRISPR/Cas9-mediated deletion of exons 2 and 3. These mice were crossed with Col8a2Q455K/Q455K mice to obtain Col8a2Q455K/Q455K/Tcf4± mice. Differential gene expression profiles in corneal endothelial cells of Col8a2Q455K/Q455K/Tcf4± and Col8a2Q455K/Q455K mice were then examined using RNA sequencing. Guttae formation and corneal endothelial cell density were assessed using contact specular microscopy. Expression of extracellular matrix (ECM) components was evaluated by qPCR and immunofluorescence analysis. Results: RNA-Seq analysis revealed 1053 differentially expressed genes between the Col8a2Q455K/Q455K/Tcf4± and the Col8a2Q455K/Q455K mice, with significant enrichment in ion channel-related pathways and downregulation of TNF-associated signaling pathways. Contact specular microscopy in 28-week-old mice demonstrated that guttae formation was significantly lower in the Col8a2Q455K/Q455K/Tcf4± mice than in the Col8a2Q455K/Q455K mice (0.71 ± 0.77% vs. 1.87 ± 1.43%, P < 0.001), whereas the corneal endothelial cell density was higher (1819 ± 170 vs. 1521 ± 292 cells/mm², P < 0.001). ECM components-particularly fibronectin and type I collagen, which are major constituents of guttae-were significantly decreased in the Col8a2Q455K/Q455K/Tcf4± mice. Conclusions: Heterozygous knockout of Tcf4 significantly suppressed the progression of the FECD phenotype, including guttae formation and endothelial cell loss, in the FECD mouse model. These findings provide in vivo support for TCF4 as a potential therapeutic target for FECD treatment.
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