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MAI SHUYI, David M Wu, Wenjun Xiong; Antagonistic interactions of Srebp2 and Lrp2 in controlling mouse eye size. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6386.
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© ARVO (1962-2015); The Authors (2016-present)
Dysregulation of lipid synthesis, transport, or turnover underlies a variety of eye diseases. Sterol regulatory element binding proteins (SREBPs) are a small family of membrane-bound transcription factors, with SREBP1 and SREBP2 regulating fatty acid and cholesterol synthesis, respectively. Low density lipoprotein-related protein 2 (LRP2) is a membrane receptor belonging to the low density lipoprotein receptor (LDLR) family and plays a pivotal role in cholesterol import. In this study, we aim to investigate the functions of Srebp2 and Lrp2 in regulating mouse eye development and function.
AAV8 was used to overexpress a constitutively active form of Srebp2 (nSrebp2) or to knock down Lrp2 by short hairpin RNA (Lrp2 shRNA) in mice. The CMV promoter was chosen to drive gene expression in different cell types in mouse eyes, including photoreceptors, retinal pigment epithelial cells, as well as non-pigmented and pigmented epithelial cells of ciliary body. AAV injections were performed subretinally to wildtype mice at postnatal day 0 (P0). Optomotor and ERG tests were performed to assess the visual function of mice. Mice were sacrificed at different ages from P7 to P90, and the axial length of the eyeballs was measured. The retinas were further processed for immunohistology with the antibodies against cone arrestin, Iba1, etc.
The eyes injected with AAV8-CMV-nSrebp2 showed buphthalmia, with significantly increased equatorial diameter. The buphthalmos phenotype started as early as P7 and lasted to P90, which was the oldest age examined. The visual acuity of the injected eyes decreased drastically, and both scotopic and photopic ERG responses were significantly dampened. Outer nuclear layer thinning and loss of cone arrestin staining suggested severe photoreceptor degeneration. Knocking down Lrp2 by AAV8-CMV-mCherry-Lrp2 shRNA induced the similar phenotypes as those by nSrebp2 overexpression. Interestingly, Srebp2 knockdown significantly rescued the buphthalmos phenotype induced by Lrp2 downregulation, although Srebp2 knockdown alone did not change eye size.
Our study suggests that Srebp2 and Lrp2, the two key genes in cholesterol metabolism, regulate eye size via unknown mechanism and that they may have antagonistic interactions. Further study will focus on the molecular and cellular mechanisms of Srebp2-Lrp2 interaction in eye size regulation.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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