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William C Gordon, Nicolas Guillermo Bazan; Early photoreceptor cell impairment upon AdipoR1 genetic ablation. Invest. Ophthalmol. Vis. Sci. 2017;58(8):268.
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© ARVO (1962-2015); The Authors (2016-present)
Adiponectin receptor 1 (AdipoR1) is associated with docosahexaenoic acid (DHA) uptake/incorporation by RPE and photoreceptors, acting as a switch to maintain homeostatic concentrations of DHA. Thus, nonfunctional AdipoR1 leads to greatly diminished DHA levels and gradual photoreceptor death. Mass spec analysis has demonstrated that all DHA-containing phosphatidylcholines of 42 to 60 carbons are virtually absent from AdipoR1-/- retinas and reduced by 50-75% of AdipoR1+/+ in RPE. This study describes the onset of photoreceptor degeneration in the AdipoR1-/- mouse.
AdipoR1+/+ and AdipoR1-/- eyes were collected, corneas slit, and immersed in Karnovsky’s fixative. Eyecups were post-fixed in OsO4, dehydrated, and plastic embedded. Thick sections were toluidine blue-contrasted and oriented for EM. Silver-gold sections were contrasted with lead and uranium salts, and imaged with a JEOL EM.
Analysis of AdipoR1-/- retinas by OCT and histology showed noticeable reduction in outer nuclear layer (ONL) thickness and photoreceptor nuclei by 1 month, with degeneration complete at 8 months. Only cone nuclei remained as a single row. Histology of P21 AdipoR1-/- retinas by light and EM showed variable time of onset and/or degeneration rate; the ONL thickness of some was 9-10 nuclei (11-12 is normal) with inner-outer segment layer thickness equal to or greater than the ONL; others had 8-9 nuclei and inner-outer segment thickness less than that of the ONL. Muller cells formed wide cytoplasmic spaces containing dark condensed material between the nuclear columns, and dark, condensed nuclei occurred loosely scattered within the inner-outer segments. Occasional thin columns of mixed nuclei extended from RPE to the ONL. EM showed healthy mitochondria, typical connecting cilia, normal-appearing basal disks, and organized disk stacks.
Lack of a functional AdipoR1 gene prevents retinal DHA accumulation, triggering photoreceptor loss by two separate means: inner-outer segments are gradually reduced uniformly across the retina as RPE clears distal debris; nuclei and related ONL material is slowly eliminated by Muller cells. Migrating cells also enter the inner-outer segment layer. Rod nuclei are eliminated from the ONL, but cone nuclei are retained, supporting the idea that DHA is required for rod homeostasis, but not that of cones.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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