Abstract
Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. While murine Nrl loss has been characterized, studies of human NRL can identify important insights for human retinal development and disease. We utilized iPSC organoid models of retinal development to molecularly define developmental alterations in a human model of NRL loss. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop S-opsin dominant photoreceptor populations. We report generation of two distinct S-opsin expressing populations in NRL null retinal organoids and identify MEF2C as a candidate regulator of cone development.
Highlights
Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood
In L75Pfs human retinal organoids, rods appeared shifted toward an S-cone fate, consistent with the Nrl−/− mouse phenotype[3,33]
In contrast to the Nrl−/− mouse, L75Pfs organoids displayed an intact outer limiting membrane (OLM) with no increase in rosette formation compared to WT organoids (Supplementary Fig. 3o–y)[3,35]
Summary
Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop Sopsin dominant photoreceptor populations. Previous murine studies have shown that Nrl loss leads to development of cone dominant retinas; an increase in S-cones[3]. Loss of NRL in humans can cause enhanced S-cone syndrome, a rare retinal disease characterized by supranormal blue cone function due to an increased proportion of S-cones and night blindness due to the absence of rods[4,5]. While previous studies have utilized scRNAseq to identify cell types of developing retinal organoids, they have not discerned distinct photoreceptor sub-populations[26,27,28]. This study further defines photoreceptor subpopulations in a human model of NRL loss and provides a platform for characterizing aberrant photoreceptor development
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