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Dysfunction of Unc119, a transducin-binding protein, leads to cone-rod dystrophy through activating JAK-STAT and NF-kB inflammatory pathways in the mouse retina

ABSTRACT: Transducin is a heterotrimeric G protein that is a component of the phototransduction cascade in rod and cone photoreceptor cells of the retina. Gnat1, a rod-specific transducin α-subunit, regulates light/dark adaptation by changing its subcellular localization depending on light. Our previous study revealed that Gnat1 translocation in rod photoreceptor cells under light/dark conditions requires E3 ligase Klhl18-mediated ubiquitination and degradation of Unc119, a Gnat1-binding protein. A mutation in the human UNC119 gene is associated with cone-rod dystrophy (CRD); however, the underlying pathological mechanism remains unclear. In this study, we generated and analyzed Unc119-deficient (Unc119−/−) mice. We found that Unc119-deficienct mouse retina exhibited progressive photoreceptor degeneration, resembling CRD in humans. We also found that Unc119 interacts with Gnat2 in cone photoreceptor cells and that Unc119 is essential for the translocation of Gnat2 to the outer segment in cone photoreceptor cells. RNA-seq and subsequent bioinformatics analysis revealed the predicted activation of the JAK-STAT and NF-κB pathways in the Unc119−/− retina. Treatment of Unc119−/− mice with curcumin, an inhibitor of the JAK-STAT and NF-κB pathways, suppressed inflammation and cone photoreceptor cell degradation in Unc119−/− retinas. Furthermore, a human CRD associated-UNC119 mutant protein inhibited the interaction between UNC119 and GNAT1 or GNAT2. Taken together, the current study suggests that UNC119 dysfunction leads to CRD by affecting the JAK-STAT and NF-κB pathways, and may advance our understanding of the pathological mechanisms of CRD.

ORGANISM(S): Mus musculus

PROVIDER: GSE282222 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:Rod and cone photoreceptors in mammalian retina are generated from common pool(s) of neuroepithelial progenitors. NRL, CRX and NR2E3 are key transcriptional regulators that control photoreceptor differentiation. Mutations in NR2E3, a rod-specific orphan nuclear receptor, lead to loss of rods, increased density of S-cones, and supernormal S-cone-mediated vision in humans. To better understand its in vivo function, NR2E3 was expressed ectopically in the Nrl-/- retina, where post-mitotic precursors fated to be rods develop into functional S-cones similar to the human NR2E3 disease. Expression of NR2E3 in the Nrl-/- retina completely suppressed cone differentiation and resulted in morphologically rod-like photoreceptors, which were not functional. Gene profiling of FACS-purified photoreceptors confirmed the role of NR2E3 as a strong suppressor of cone genes and an activator of a subset of rod genes (including rhodopsin) in vivo. Ectopic expression of NR2E3 in cone precursors and differentiating S-cones of wild type retina also generates rod-like cells. The dual regulatory function of NR2E3 is not dependent upon the presence of NRL and/or CRX, but on the timing and level of its expression. Our studies reveal a critical role of NR2E3 in establishing functional specificity of post-mitotic photoreceptor precursors during retinal neurogenesis. Experiment Overall Design: We mated the Crx::Nr2e3/Nrlko mice with the Nrl::GFP transgenic mice, in which the expression of GFP is driven by an Nrl promoter. Mouse retinas were dissected at 4 wk. GFP+ photoreceptors were enriched by FACS (FACSAria, BD Biosciences, Franklin Lakes, NJ). RNA was extracted from 1~5x105 flow-sorted cells using Trizol (Invitrogen). Total RNA (40-60 ng) was used for linear amplification with Ovation Biotin labeling system (Nugen), and 2.75 ug of biotin-labeled fragmented cDNA was hybridized to mouse GeneChips MOE430.2.0 (Affymetrix) having 45,101 probesets (corresponding to over 39,000 transcripts, and 34,000 annotated mouse genes). Experiment Overall Design: Four independent samples were used at 4 weeks. We normalized Experiment Overall Design: Crx::Nr2e3/Nrl-ko-Gfp data along with Nrl-ko-Gfp 4 weeks samples ( 4 replicates, refer to Series submission GSE4051). The normalized data was then subjected to two stage analysis based on False Discovery Rate Confidence Interval (FDR-CI) for screening differentially expressed genes (24, 27) with a minimum fold change of 4.

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Dysfunction of Unc119, a transducin-binding protein, leads to cone-rod dystrophy through activating JAK-STAT and NF-kB inflammatory pathways in the mouse retina

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