F22GENES AND PATHWAYS ALTERED BY COCAINE IDENTIFIED THROUGH HUMAN TRANSCRIPTOMIC STUDIES

Abstract

NR2E3 encodes an orphan nuclear receptor that plays a dual function as both transcriptional activator and repressor in photoreceptors, being necessary for cone fate inhibition as well as rod differentiation and homeostasis. Mutations in this gene cause retinitis pigmentosa (RP), enhanced S cone syndrome (ESCS) and Goldmann-Favre syndrome (GFS). There is one reported Nr2e3 isoform that contains all 8 exons and a second –previously unreported– shorter isoform, which only spans the first 7 exons and whose function is still unknown. In this data article, we designed and generated two new mouse models by targeting exon 8 of Nr2e3 using the CRISPR/Cas9-D10A nickase in order to dissect the role of the two isoforms in Nr2e3 function and elucidate the different disease mechanisms caused by NR2E3 mutations. This strategy generated several modified alleles that altered the coding sequence of the last exon thereby affecting functional domains of the transcription factor. Allele Δ27 is an in-frame deletion of 27 bp that ablates the dimerization domain, whereas allele ΔE8 (full deletion of exon 8), produces only the short isoform that lacks the dimerization and repressor domains. Morphological and functional alterations of both Δ27 and ΔE8 mutants are reported in the associated research article “Nr2e3 functional domain ablation by CRISPR-Cas9D10A identifies a new isoform and generated Retinitis Pigmentosa and Enhanced S-cone Syndrome models” (Aísa-Marín et al., 2020).