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Marie-Audrey Ines Kautzmann, Khanh Do, Nicolas G Bazan; Gender analysis of the transcriptomes of AdipoR1 and MFRP deficient mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4506.
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© ARVO (1962-2015); The Authors (2016-present)
Genetic ablation of Adiponectin receptor 1 (AdipoR1) or Membrane frizzled-related protein (MFRP) in mice leads to the reduction of docosahexaenoic acid (DHA) and very-long-chain polyunsaturated fatty acids (VLC-PUFAs) in the RPE and retina. VLC-PUFA omega-3s are precursors of the bioactive mediators elovanoids, hence, their reduction in mutant animals leads to photoreceptor cells (PRCs) loss. The aim of this study is to uncover gene networks that are dysregulated in these mutant animals, to better understand how homeostasis to sustain PRC integrity is regulated.
Total RNA was extracted from the retinas and eyecups of 1 month-old males and females wild type (WT), AdipoR1 and MFRP mutant mice. Quantitative polymerase chain reaction (qPCR) was used to determine the differential expression of cell death-related genes. Expression analysis was performed using the ΔΔCt method and geometric average of housekeeping genes.
In comparison to WT, qPCR analysis revealed >10-fold upregulation of Casp1 in the retina of AdipoR1 KO males and females, 5-fold increase in MFRP KO males and 3-fold increase in females. Casp8 was 2-fold higher in both males and females AdipoR1 and MFRP mutants. Fas was increased by 5-fold in AdipoR1 KO males, and by 2-fold in females. In MFRP KO animals, Fas was increased by 4-fold in males and barely increased in females compared to the WT. In the RPE, Casp8 showed 2-fold increase in both mutant males, however the expression in the females was not significant. Interestingly, NF-kB was increased only in the RPE of mutant males.
These data show that the depletion of AdipoR1 or MFRP affects the retinal transcriptome differently than the RPE, by upregulating specific types of inflammatory genes. The fact that males displayed higher gene expression levels than the females could mean that they are more sensitive to DHA depletion or that the females activate some temporary compensatory mechanisms to cope with the mutation but will eventually fail and lead to retinal degeneration. Modulation of the inflammatory response under these conditions by the newly discovered elovanoids could rescue their phenotype as these lipid mediators regulate inflammation and restorative cell survival (Jun et al., 2017; Bhattacharjee et al., 2017).
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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