PURPOSE: Retinitis pigmentosa (RP) is a hereditary retinal disease characterized by progressive degeneration of photoreceptor cells (PRCs). Identifying potential pathogenic genes and understanding the mechanisms of PRC degeneration are essential for improving diagnosis and treatment. Cytoplasmic dynein 1, responsible for retrograde axonal transport along microtubules, plays critical roles in neuronal function. This study utilized dync1h1-deficient zebrafish to investigate its roles in PRC morphogenesis and degeneration. METHODS: Heterozygous and homozygous dync1h1-deficient zebrafish were confirmed through Sanger sequencing. Morphological changes and retinal phenotypes were assessed through histological analysis. RNA sequencing and bioinformatics were used to explore molecular mechanisms in dync1h1-/- zebrafish, with endoplasmic reticulum (ER) stress and apoptosis pathways validated in vivo. RESULTS: Dync1h1-/- zebrafish exhibit severe developmental defects, including microphthalmia, disorganized retinal lamination, and PRC apoptosis. In dync1h1+/-, mild but progressive growth retardation and PRC defects were observed. Dync1h1 loss impaired retrograde axonal transport, leading to defects in cilium biogenesis and transport disorder of phototransduction proteins in PRCs. This triggered ER stress, activating BiP-ATF4-CHOP signaling pathway and leading to PRC degeneration. CONCLUSIONS: Dync1h1 is essential for maintaining retrograde axonal transport and proper trafficking of phototransduction proteins in PRCs. Non-resolving ER stress-induced PRC apoptosis is a key factor in DYNC1H1-associated retinal degeneration. This study provides important insights into the precise diagnosis and may help in the development of targeted therapies for retinal degenerative diseases.