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Weiyong Shen, So-Ra Lee, Michelle X. Yam, Nigel L Barnett, Ashish Easow Mathai, Rui Zhang, Ling Zhu, James Hurley, Jianhai Du, Pankaj Seth, Yoshio Hirabayashi, Shigeki Furuya, Mark C Gillies; The consequences of selectively knocking down key metabolic genes in Müller cells of the mouse retina. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1492.
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© ARVO (1962-2015); The Authors (2016-present)
Derangement of glucose metabolism is a potential cause of photoreceptor degeneration. We have previously shown that selectively ablating Müller cells leads to photoreceptor degeneration, indicating that Müller cells are critical for their survival (Shen et al. J Neurosci 2012). This project aimed to study the consequences of selectively knocking down key metabolic genes in Müller cells of the mouse retina.
Transgenic mice for inducible Müller cell-specific gene targeting (Rlbp1-CreER mice) were crossed with mice carrying floxed metabolic genes including insulin receptor (IR), hexokinase 2 (Hk2), lactate dehydrogenase A (LDH-A), pyruvate dehydrogenase E1α (PDH-E1α) and phosphoglycerate dehydrogenase (PHGDH). Rlbp1-CreER mice crossed with Cre reporter mice were used as controls. Changes in target gene expression and the rod and cone photoreceptors were studied by immunostaining and Western blots. Retinal function was assessed by dark-adapted flash electroretinography (ERG).
Double label immunofluorescent staining indicated that Müller cells expressed IR, Hk2 and PHGDH but not LDH-A and PDH-E1α. Knocking down IR, HK2 and PHGDH in Müller cells resulted in photoreceptor degeneration 3-4 weeks after tamoxifen-induced Cre expression, as evidenced by the loss of cone photoreceptor apical processes after staining retinas with fluorescently labelled peanut agglutinin and antibodies against blue- and red-green opsin. These changes were accompanied by impaired retinal function as measured by ERG. We also found that knocking down PHGDH appeared to produce more profound effects on photoreceptor degeneration compared with knocking down IR and Hk2 in Müller cells. We did not observe any retinal abnormalities after crossing Rlbp1-CreER mice with transgenic lines carrying floxed LDH-A and PDH-E1α genes.
Our data suggest that Müller cells may use glucose through the upstream of aerobic glycolysis and the serine/glycine metabolic pathway to support photoreceptors in the mammalian retina.
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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