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Hyperactive PDGFRβ signaling induces cataractogenesis via TGFβ and STAT5-IGF1

ABSTRACT: Introduction: Cataracts are the world’s leading cause of reversible blindness. Although cataract formation is commonly initiated by lens fiber cell defects, cataractogenesis can be characterized by aberrant proliferation and migration of lens epithelial cells, particularly in posterior capsule opacification. Subsequent overproduction of extracellular matrix components such as fibronectin and collagen by epithelial cells is associated with fibrosis of the lens. Little is known about the role of platelet-derived growth factor receptor β (PDGFRβ) in lens fibrosis. Here, we investigated mice with a conditional knock-in driving mesenchymal-specific PDGFRβ hyperactivation (Fsp1-cre;Pdgfrb+/D849V), which consistently develop cataracts at a young age. Methods: Lenses from Fsp1-cre;Pdgfrb+/D849V mice and age-matched controls were dissected and visualized via microscopy from 9-15 weeks. Early transcriptional changes were investigated between 10-12 day old Fsp1-cre;Pdgfrb+/D849V and control mice via RNA sequencing followed by gene set enrichment analysis. Confirmation of RNA sequencing results and mechanistic investigation of PDGFRβ-induced cataractogenesis were determined in lenses isolated from 15-week-old Fsp1-cre;Pdgfrb+/D849V and control mice. Results: Gross examination of cataractous lenses from Fsp1-cre;Pdgfrb+/D849V mice revealed complete opacification by 15 weeks of age compared to no opacification in age-matched controls. Structural changes in the anterior, equatorial, and posterior lens were observed in histology. RNA sequencing revealed significant enrichment of gene sets related to extracellular matrix deposition and reorganization. Mechanistic investigation revealed major roles for TGFβ, SOCS2, and STAT5-IGF1 signaling axes in PDGFRβ-induced cataract formation. Conclusion: PDGFRβ promoted cataractogenesis by modulating pro-fibrotic extracellular matrix changes, likely through TGFβ, SOCS2, and the STAT5-IGF1 pathways. Future experiments will delineate the precise role of the STAT5-IGF1 signaling pathway in PDGFRβ-mediated fibrosis and the interplay between PDGFRβ and TGFβ in the lens and whether this signaling is targetable to modulate cataractogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE302408 | GEO | 2025/07/18

REPOSITORIES: GEO

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Project description:Glutathione (GSH) is a critical endogenous antioxidant that protects against intracellular oxidative stress. As such, pathological alterations in GSH levels are linked to a myriad of diseases including cancer, neurodegeneration and cataract. The rate limiting step in GSH biosynthesis is catalyzed by the glutamate cysteine ligase catalytic subunit (GCLC). The high expression of GCLC in the lens supports the synthesis of millimolar concentrations of GSH in this tissue. Herein, we describe the morphological consequences of deleting (knocking out) Gclc from surface ectoderm-derived ocular tissues (using the Le-Cre transgene; Gclc KO) which includes an overt microphthalmia phenotype and severely disrupted formation of multiple ocular structures (i.e., cornea, iris, lens, retina). Controlling for the Le-Cre transgene revealed that the deletion of Gclc significantly exacerbated the microphthalmia phenotype in Le-Cre hemizygous mice and resulted in dysregulated gene expression that was unique to only the lenses of KO mice. We further characterized the impaired lens development by conducting an RNA-seq experiment on KO and Gclc control (CON) mouse lens at the day of birth. RNA-sequencing revealed significant differences between Gclc knockout (KO) and Gclc control (CON) lenses, including down-regulation of crystallins and lens fiber cell identity genes, and up-regulation of lens epithelial cell identity genes. In addition, genes related to the immune system (e.g., immune system process, inflammatory response, neutrophil chemotaxis) were upregulated, and genes related to eye/lens development were downregulated. TRANSFAC analysis of differentially expressed genes (DEGs) in the lens of Gclc KO mice implicated PAX6 as a key upstream regulator of Gclc KO sensitive genes. This was further supported by a strong positive correlation between the transcriptomes of the lenses of Gclc KO and Pax6 KO mice. Strikingly, the dysregulation of PAX6-regulated genes in Gclc KO mice was observed despite no change in the ocular localization of PAX6 or decrease in the expression of PAX6 in the lens. In vitro experiments demonstrated that suppression of intracellular GSH concentrations resulted in impairment of PAX6 transactivation activity. Taken together, the present results elucidate a novel mechanism wherein intracellular GSH concentrations may modulate PAX6 activity.

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Hyperactive PDGFRβ signaling induces cataractogenesis via TGFβ and STAT5-IGF1

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