To facilitate vision, a crucial process involves the recycling of the visual pigment, 11-cis-retinal, which involves two biological mechanisms: outer segment phagocytosis and the photopic visual cycle. These processes involve the cellular interplay of photoreceptors, retinal pigmented epithelium (RPE), and Müller glia. Mutations in genes within these processes frequently lead to inherited retinal diseases (IRD).
Our study employs genetic techniques in zebrafish models to investigate the consequences of mutations in RAB28, RLBP1, RGR, and EMC1. Rab28 knockout zebrafish exhibit defective outer segment phagocytosis and diminished retinoid levels. Notably, the defect can be corrected by cone-
specific expression of Rab28, implying its vital role in cone photoreceptor function. Rlbp1b knockout zebrafish mimic the ‘night blindness’ reported by RLBP1 patients, displaying visual impairments under dim light conditions. In addition, we have generated rgr knockout zebrafish through CRISPR-
Cas9 mutagenesis and are currently investigating potential visual defects.
To evaluate the disease relevance of these genes, we have generated humanized zebrafish lines. These lines lack the corresponding zebrafish gene and express either the wild-type human protein or variants linked to inherited retinal degeneration. Furthermore, we’ve developed an emc1 defective zebrafish line through chemical mutagenesis, and shown it has defective vision via the optokinetic response assay.
These zebrafish lines provide us with interesting insights into the role of these genes within their biological process and serve as useful tools for both understanding these processes in more detail and drug discovery going forward
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