June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Postnatal eye size in mice is controlled by SREBP2-mediated transcriptional repression of Lrp2 and Bmp2
Author Affiliations & Notes
  • MAI SHUYI
    City University of Hong Kong, Hong Kong, Hong Kong, Hong Kong
  • Xiaoxuan Zhu
    City University of Hong Kong, Hong Kong, Hong Kong, Hong Kong
  • Esther Yi Ching Wan
    City University of Hong Kong, Hong Kong, Hong Kong, Hong Kong
  • Shengyu Wu
    City University of Hong Kong, Hong Kong, Hong Kong, Hong Kong
  • Jesslyn Nagalin Yonathan
    City University of Hong Kong, Hong Kong, Hong Kong, Hong Kong
  • Jun Wang
    City University of Hong Kong, Hong Kong, Hong Kong, Hong Kong
  • Ying Li
    Taiyuan University of Technology, Taiyuan, Shanxi, China
  • Jessica Yuen Wuen Ma
    The Hong Kong Polytechnic University, Hong Kong, Hong Kong
  • Bing Zuo
    The Hong Kong Polytechnic University, Hong Kong, Hong Kong
  • Dennis Yan-yin Tse
    The Hong Kong Polytechnic University, Hong Kong, Hong Kong
  • Pui-Chi Lo
    City University of Hong Kong, Hong Kong, Hong Kong, Hong Kong
  • Xin Wang
    The Chinese University of Hong Kong, Hong Kong, Hong Kong
  • Kui Ming Chan
    City University of Hong Kong, Hong Kong, Hong Kong, Hong Kong
  • David M Wu
    Harvard Medical School, Boston, United Kingdom
  • Wenjun Xiong
    City University of Hong Kong, Hong Kong, Hong Kong, Hong Kong
  • Footnotes
    Commercial Relationships   MAI SHUYI None; Xiaoxuan Zhu None; Esther Wan None; Shengyu Wu None; Jesslyn Yonathan None; Jun Wang None; Ying Li None; Jessica Ma None; Bing Zuo None; Dennis Tse None; Pui-Chi Lo None; Xin Wang None; Kui Ming Chan None; David Wu None; Wenjun Xiong None
  • Footnotes
    Support  Hong Kong RGC General Research Fund (GRF) 11102922
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 960. doi:
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      MAI SHUYI, Xiaoxuan Zhu, Esther Yi Ching Wan, Shengyu Wu, Jesslyn Nagalin Yonathan, Jun Wang, Ying Li, Jessica Yuen Wuen Ma, Bing Zuo, Dennis Yan-yin Tse, Pui-Chi Lo, Xin Wang, Kui Ming Chan, David M Wu, Wenjun Xiong; Postnatal eye size in mice is controlled by SREBP2-mediated transcriptional repression of Lrp2 and Bmp2. Invest. Ophthalmol. Vis. Sci. 2023;64(8):960.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Eye size is a key parameter of visual function, but the precise mechanisms of eye size control remain poorly understood. In a study aiming to understand the role of lipid synthesis in retina development and diseases, we made an unexpected discovery that the lipogenic transcription factor sterol regulatory element-binding protein 2 (SREBP2) has a function in eye size regulation. SREBP2 is expressed in the neural retina and retinal pigment epithelium (RPE) cells, but its function in eye development remains elusive. In this study, we investigated the role of SREBP2 and its downstream signaling pathway in regulating eye size in mice.

Methods : Adeno-associated virus(AAV)-mediated gene transfer was used to target gene expression or knock down specifically in the RPE using the bestrophin 1 promoter. Subretinal injections were performed to neonatal mice. Mice were sacrificed at postnatal day 14, and their eyes were enucleated, and the axial length of the eyeballs was measured. RNA-sequencing analysis, ChIP-qPCR, luciferase reporter assay, real-time PCR, and western blot were used to investigate the downstream targets of Srebp2. EdU incorporation assay was performed to quantify cell proliferation, and the number of EdU-positive cells in the retina, RPE/choroid and sclera was quantified.

Results : Overexpression of a constitutively active form of Srebp2 (nSrebp2) in the RPE cells of postnatal mice leads to extremely enlarged eye globes. Taking this observation as a starting point, we reveal that Lrp2, a gene that is known to restrict eye overgrowth, is transcriptionally repressed by SREBP2. Transcriptome analysis and functional assays identified that BMP2 is the downstream effector of both Srebp2 and Lrp2, and the level of Bmp2 in the RPE is the key determinant of eye size. As the upstream regulator, SREBP2 transcriptionally represses Bmp2. Over postnatal development, the levels of Lrp2 and Bmp2 transcripts increase and the SREBP2 protein level decreases. Notably, RPE-specific Bmp2 overexpression by AAV can effectively prevent the eye enlargement and retinal thinning caused by Lrp2 loss.

Conclusions : Our study suggests that rapid postnatal eye size increase is governed by an RPE-derived signaling pathway, which consists of both positive and negative regulators of eye growth. Overall, this study unveils an essential role of the SREBP2-LRP2-BMP2 signaling in the RPE in determining eye size.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

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