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While postnatal growth of lens is based on the addition of lens fibre cells (LFCs) supplemented by proliferation and differentiation of lens epithelial cells (LECs), it remains unknown how these cellular processes change in highly myopic eyes and what signalling pathways may be involved. Single\u2010cell RNA sequencing was performed and a total of 50,375 single cells isolated from the lens epithelium of mouse highly myopic and control eyes were analysed to uncover their underlying transcriptome atlas. The proportion of LFCs was significantly higher in highly myopic eyes. Meanwhile, <jats:italic>Notch2<\/jats:italic> signalling was inhibited during lineage differentiation trajectory towards LFCs, while <jats:italic>Notch2<\/jats:italic> predominant LEC cluster was significantly reduced in highly myopic eyes. In consistence, <jats:italic>Notch2<\/jats:italic> was the top down\u2010regulated gene identified in highly myopic lens epithelium. Further validation experiments confirmed NOTCH2 downregulation in the lens epithelium of human and mouse highly myopic eyes. In addition, <jats:italic>NOTCH2<\/jats:italic> knockdown in primary human and mouse LECs resulted in enhanced differentiation towards LFCs accompanied by up\u2010regulation of MAF and CDKN1C. These findings indicated an essential role of NOTCH2 inhibition in lens overgrowth of highly myopic eyes, suggesting a therapeutic target for future interventions.<\/jats:p>","DOI":"10.1111\/cpr.13412","type":"journal-article","created":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T04:15:17Z","timestamp":1675138517000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Single\u2010cell <scp>RNA<\/scp> sequencing: Inhibited Notch2 signalling underlying the increased lens fibre cells differentiation in high myopia"],"prefix":"10.1111","volume":"56","author":[{"given":"Yunqian","family":"Yao","sequence":"first","affiliation":[{"name":"Eye Institute and Department of Ophthalmology Eye &amp; ENT Hospital, Fudan University  Shanghai China"},{"name":"National Health Center Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia Chinese Academy of Medical Sciences  Shanghai China"},{"name":"Shanghai 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