Abstract
Neural retina leucine zipper (NRL) is an essential gene for the fate determination and differentiation of the precursor cells into rod photoreceptors in mammals. Mutations in NRL are associated with the autosomal recessive enhanced S-cone syndrome and autosomal dominant retinitis pigmentosa. However, the exact role of Nrl in regulating the development and maintenance of photoreceptors in the zebrafish (Danio rerio), a popular animal model used for retinal degeneration and regeneration studies, has not been fully determined. In this study, we generated an nrl knockout zebrafish model via the CRISPR-Cas9 technology and observed a surprising phenotype characterized by a reduced number, but not the total loss, of rods and over-growth of green cones. We discovered two waves of rod genesis, nrl-dependent and -independent at the embryonic and post-embryonic stages, respectively, in zebrafish by monitoring the rod development. Through bulk and single-cell RNA sequencing, we characterized the gene expression profiles of the whole retina and each retinal cell type from the wild type and nrl knockout zebrafish. The over-growth of green cones and mis-expression of green-cone-specific genes in rods in nrl mutants suggested that there are rod/green-cone bipotent precursors, whose fate choice between rod versus green-cone is controlled by nrl. Besides, we identified the mafba gene as a novel regulator of the nrl-independent rod development, based on the cell-type-specific expression patterns and the retinal phenotype of nrl/mafba double-knockout zebrafish. Gene collinearity analysis revealed the evolutionary origin of mafba and suggested that the function of mafba in rod development is specific to modern fishes. Furthermore, the altered photoreceptor composition and abnormal gene expression in nrl mutants caused progressive retinal degeneration and subsequent regeneration. Accordingly, this study revealed a novel function of the mafba gene in rod development and established a working model for the developmental and regulatory mechanisms regarding the rod and green-cone photoreceptors in zebrafish.
Highlights
Neural retina leucine zipper (NRL) is an essential gene for the generation and function of rod cells in mice and humans
The rod cell formation at the postembryonic is driven by the mafba gene, which has not been reported to play a role in rod cells
In addition to the reduced number of rod cells, deletion of nrl results in the emergence of rod/green-cone hybrid cells and an increased number of green cones
Summary
Vision is involved in many fundamental behaviors of animals such as navigation, foraging, predator avoidance, and mate choice [1]. In humans, inherited retinal diseases are a major cause of irreversible vision impairment and blindness, causing serious physical discomfort and mental problems in the patients, who face a heavy economic burden [2,3]. There are two types of light-sensing cells named rod and cone photoreceptors in vertebrate eyes. Rods and cones are derived from the same progenitor cells, which are regulated by several extrinsic signals and intrinsic transcription factors, such as CRX, NRL, and NR2E3 [6,7]. Exploring the fundamental mechanisms controlling the fate determination and differentiation of photoreceptors in diverse animal models is of great value for understanding the development and evolution of photoreceptors and the pathogenesis of retinal degenerative diseases
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