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Pascal Escher, Emanuele Bulla, Beatrice Steiner, Despina Kokona, Martin Sebastian Zinkernagel, Giulia Venturini; Molecular and cellular mechanisms in Nr2e3-linked retinal degenerations. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4898.
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© ARVO (1962-2015); The Authors (2016-present)
Description and analysis of mouse models of Nr2e3-linked retinal degenerations, and functional analysis of potential underlying molecular mechanisms
We characterized retinal degeneration in C57BL/6J Nr2e3rd7/rd7 mice, and in newly generated ‘knock-in’ mice with targeted modifications in the DNA-binding domain (DBD) and ligand-binding domain (LBD); in vivo, by fundus photography, optical coherence tomography (OCT), electroretinography (ERG) and fluorescein angiography; post mortem by histology and immunohistochemistry. Additional in vitro analyses included RNA expression profiling, Western blotting and BRET (bioluminescence resonance energy transfer) assays.
The photoreceptor-specific nuclear receptor Nr2e3 is not expressed in Nr2e3rd7/rd7 mice, a mouse model of the recessively inherited retinal degeneration enhanced S-cone sensitivity syndrome (ESCS), with rosette-like structures present in the outer nuclear layer and a slow loss of photoreceptors. Retinal spots and ‘rosettes’ first appear at postnatal day (P) 12 in the dorsal retina and reach maximal expansion at P21. At that age, the dorso-ventral M-cone gradient and the opposing ventro-dorsal S-cone gradient are present. Microglial cells and monocytes/macrophages are detected within ‘rosettes’. The highest density in rosettes is observed within a region located between 100 and 350 µM with respect to the optic nerve head where they persist the longest. Rosettes disappear by 9 to 12 months, and slow photoreceptor degeneration, at a rate of an approximately 3 % loss of outer nuclear layer thickness per month, is observed up to 31 months of age. The knock-in mouse model with a targeted missense mutation in the LBD shows an identical phenotype to the Nr2e3rd7/rd7 mice, whereas a targeted missense mutation in the DBD exhibits a more severe phenotype, functionally and anatomically. The impact of mutations in the LBD on cofactor assembly were further analyzed in vitro.
The newly generated knock-in mouse models allow to delineate the contribution of the Nr2e3 DBD and the LBD to retinal degeneration, in comparison to the absence of the Nr2e3 transcription factor (Nr2e3rd7/rd7).
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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