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Salma Ferdous, Isabelle Gefke, Jeffrey H Boatright, Hans E Grossniklaus, John M Nickerson; Characterization and functional analysis of Lsd1 within the murine eye. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2346. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To assess the role of lysine specific demethylase 1 (Lsd1) in proper murine ocular development by determining its expression level and localization. Lsd1 is an epigenetic protein that demethylates histone modifications H3K4 mono- and di-methylation (H3K4me1/2) and plays a role in neuronal development. Inhibition of Lsd1 is known to attenuate rod photoreceptor development; however, its general role in ocular development is unknown.
Immunohistochemistry and western blotting for Lsd1 and H3K4me1/2 expression was conducted on murine eyes across numerous developmental time-points to determine localization and relative levels.
Lsd1 and H3K4me1/2 had highest retinal expression at post-natal day 2 (P2), concurrent with retinogenesis and beginning of terminal retinal differentiation. Expression gradually decreases over developmental time until a basement level of ~25% is reached at P36. Lsd1 is expressed at uniformly high levels in all cells within the developing murine retinoblast, as is H3K4me1/2, however, variation in Lsd1 expression is seen among different cell types in the mature retina. In contrast H3K4me1/2 had high expression in the mature retina. At P36 there was variable Lsd1 expression in the GCL, uniform expression in INL, and then dichotomous expression in the ONL, with cones expressing relatively high Lsd1 levels and rods expressing relatively low levels in a ring. Additionally, Lsd1 was variably expressed in the lens, cornea, and retinal pigment epithelium (RPE).
Due to its high expression during early retinal development, Lsd1 may play a critical role in orchestrating the differentiation of various retinal subtypes. Variability in Lsd1 expression among different mature retinal subtypes may be indicative of their unique transcriptomes and epigenetic landscapes. Specifically, in nocturnal animals, rod and cone photoreceptors have inverse chromatin architectures which may account for their distinct Lsd1 expression pattern. This differential expression of Lsd1 in the photoreceptors subtypes may be causative or consequential and future studies deleting Lsd1 from these cell types warrant investigation. The dysfunction and death of photoreceptors is the primary cause of visual impairment and blindness in retinal diseases, thus pharmacological Lsd1 inhibitors, which are neuroprotective in glaucoma, may be a potential therapeutic avenue for retinal degenerative disorders.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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