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Original research
Dysfunction of VIPR2 leads to myopia in humans and mice
  1. Fuxin Zhao1,2,
  2. Qihang Li1,2,
  3. Wei Chen3,4,
  4. He Zhu1,2,
  5. Dengke Zhou1,2,
  6. Peter Sol Reinach1,2,
  7. Zhenglin Yang5,
  8. Mingguang He6,
  9. Anquan Xue1,2,
  10. Deng Wu4,
  11. Tianzi Liu4,
  12. Qian Fu1,2,
  13. Changqing Zeng4,
  14. Jia Qu1,2,
  15. Xiangtian Zhou1,2
  1. 1School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
  2. 2The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, China
  3. 3Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
  4. 4Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, The Chinese Academy of Sciences, Beijing, China
  5. 5The Key Laboratory for Human Disease Gene Study of Sichuan Province and Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
  6. 6State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
  1. Correspondence to Dr Xiangtian Zhou, Wenzhou, Zhejiang, China; zxt{at}mail.eye.ac.cn

Abstract

Background Myopia is the leading cause of refractive errors. As its pathogenesis is poorly understood, we determined if the retinal VIP-VIPR2 signalling pathway axis has a role in controlling signalling output that affects myopia development in mice.

Methods Association analysis meta-study, single-cell transcriptome, bulk RNA sequencing, pharmacological manipulation and VIPR2 gene knockout studies were used to clarify if changes in the VIP-VIPR2 signalling pathway affect refractive development in mice.

Results The SNP rs6979985 of the VIPR2 gene was associated with high myopia in a Chinese Han cohort (randomceffect model: p=0.013). After either 1 or 2 days’ form deprivation (FD) retinal VIP mRNA expression was downregulated. Retinal single-cell transcriptome sequencing showed that VIPR2 was expressed mainly by bipolar cells. Furthermore, the cAMP signalling pathway axis was inhibited in some VIPR2+ clusters after 2 days of FD. The selective VIPR2 antagonist PG99-465 induced relative myopia, whereas the selective VIPR2 agonist Ro25-1553 inhibited this response. In Vipr2 knockout (Vipr2-KO) mice, refraction was significantly shifted towards myopia (p<0.05). The amplitudes of the bipolar cell derived b-waves in 7-week-old Vipr2-KO mice were significantly larger than those in their WT littermates (p<0.05).

Conclusions Loss of VIPR2 function likely compromises bipolar cell function based on presumed changes in signal transduction due to altered signature electrical wave activity output in these mice. As these effects correspond with increases in form deprivation myopia (FDM), the VIP-VIPR2 signalling pathway axis is a viable novel target to control the development of this condition.

  • eye diseases
  • genetics
  • genetics
  • medical
  • ophthalmology
  • RNA-Seq

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Footnotes

  • Contributors XZ, CZ and JQ designed and supervised the study; FZ, QL, HZ, DZ and QF performed the animal and analysed the data; FZ and AX enrolled the high myopia patients from Wenzhou and analysed the data; ZY enrolled the high myopia patients and analysed the data from Sichuan Cohort; MH enrolled the high myopia patients and analysed the data from Guangzhou Cohort; TL and WC performed the genotyping and meta-study; FZ, DW and WC performed single cell transcriptome sequencing and data analysis. FZ wrote original draft; FZ, PR, CZ, JQ and XZ reviewed and revised the manuscript; FZ, JQ and XZ acquired funding. All authors have read and approved the current version of this manuscript and have agreed to its submission.

  • Funding The study was supported by the National Natural Science Foundation of China grants 81570881 and 81170880 (FZ), 81670886 and 81422007 (XZ) and 81670876 (JQ); the National Key Research and Development Program of China grant No. 2016YFC0905201 (JQ) and No. 2016YFC0901504 (XZ); Zhejiang Provincial Natural Science Foundation of China grants LY18H120005 (FZ); Zhejiang Province Program for the Cultivation of High-Level Innovative Health Talents (XZ); and The National Young Excellent Talents Support Program (XZ).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Institutional Review Board of Eye Hospital, Wenzhou Medical University Wenzhou, Zhejiang, China (Approval number: KYK-2015-01); Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; and Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. Informed consent was obtained from each subject. The study was approved by the Animal Care and Ethics Committee at Wenzhou Medical University (Wenzhou, Zhejiang, China).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. Data are available on reasonable request. Transcriptome sequencing data have been deposited in the BIG Data Center database (http://bigd.big.ac.cn/bioproject/), accession number: subCRA002552. All other data that support our findings are available from the corresponding authors on request.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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