Retinal degeneration across developmental stages in zebrafish knock-out for impg2: a morphological and ultrastructural investigation

Retinitis pigmentosa (RP) is among the most common inherited retinal dystrophies, characterized by the progressive degeneration of photoreceptors. Recent studies have linked nonsense mutations in the interphotoreceptor matrix proteoglycan 2 (IMPG2) gene to autosomal recessive forms of RP in humans. IMPG2 encodes a proteoglycan localized within the interphotoreceptor matrix (IPM), a specialized extracellular compartment that surrounds the photoreceptor outer segments and ellipsoids, likely contributing to IPM structural integrity through interactions with other matrix components. In this study, we employed zebrafish as a model organism to investigate the impact of IMPG2 deficiency on extracellular matrix organization, photoreceptor degeneration, and retinal functional impairment. Due to the similarity between zebrafish retinal architecture and the human macula, this model offers valuable insights into retinal pathophysiology. We characterized the two zebrafish IMPG2 paralogs, impg2a and impg2b, and evaluated the morphological and ultrastructural consequences of their loss in knockout larvae at 7 days post-fertilization (dpf) and juveniles at 1 month post-fertilization (mpf). Our analyses revealed significant abnormalities in both the retinal pigment epithelium (RPE) and photoreceptor layers, suggesting that enhanced photoreceptor degeneration may impair RPE function and contribute to disease pathogenesis. These findings support the use of impg2-deficient zebrafish as a reliable model for screening potential therapeutic compounds aimed at preserving IPM integrity and mitigating photoreceptor degeneration, with broad relevance to the treatment of retinal dystrophies.