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Emeline F Nandrot, Quentin Rieu, Solène Roux, Salomé Réty, Sébastien Augustin, Florian Sennlaub, Ira Tabas; Retinal atrophy phenotypes associated with light sensitivity and inflammation in the new MerTK-cleavage resistant mouse model. Invest. Ophthalmol. Vis. Sci. 2020;61(7):662.
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© ARVO (1962-2015); The Authors (2016-present)
The MerTK tyrosine kinase receptor is a key element of the retinal pigment epithelial (RPE) phagocytic machinery required for photoreceptors survival. Recently, we showed this receptor is subjected to cleavage of its extracellular domain as a way of finely controlling its function. We thus hypothesized that absence of this regulation process would lead to gradual deficits in the retinal homeostasis. Hence, we investigated the ocular phenotype of MerTK cleavage-resistant (MerTK-CR) mice for which the cleavage site has been abrogated.
MerTK-CR and control mice were monitored between the ages of 3-12 months and at 18 months using fundus photography (FP) and autofluorescence (AF) detection, optical coherence tomography (OCT), scanning laser ophthalmoscopy (SLO), electroretinography (ERG) and optokinetic (OKR) behavioral tests. Paraffin-embedded and electron microscopy (EM) sections were processed at all ages or 18 months. Cellular respiration of live RPE/choroid and retina tissues was evaluated using the Agilent MitoXpress Xtra kit. Survival of bone-marrow macrophages (BMMs) was assessed in pig primary RPE co-cultures.
The first cohort followed monthly by FP showed large degenerescence areas in the central retina close to the optic nerve associated with AF from 4 months of age in males and then in females. By OCT, we detected thinning of the photoreceptor layer and macrophage infiltration. However, the second cohort evaluated by ERG did not show any visual deficiency or fundus anomalies before 12 months. In a separate cohort studied by OCT only phenotypes appeared much later, hence MerTK-CR mice might be light-sensitive. At the EM level, RPE anomalies were detected, including phagosomes retained in the apical area and abnormal mitochondria. However, mitochondrial function seems to be normal in both RPE/choroid and retinal tissues. MerTK-CR BMMs do not survive more than controls in pig primary RPE co-cultures, suggesting that observed macrophages could be linked to decreased RPE immunosuppressivity.
Experiments will test the level of light sensitivity of MerTK-CR mice. The phagocytic profile and immunosuppressivity of MerTK-CR RPE cells will be assessed both in vitro and in vivo. All together, the MerTK-CR mouse model displays a novel phenotype that could prove useful to understand deregulation of RPE function associated with inflammation.
This is a 2020 ARVO Annual Meeting abstract.
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