Anatomical And Transcriptional Alterations In The Mouse Choroid Induced By All-Trans Retinoic Acid

Choroidal all-trans retinoic acid (atRA) has been proposed as a regulator of scleral remodeling during myopia development. However, the choroidal effects of atRA and the underlying mechanisms remain poorly understood. Here, we aim to characterize choroidal changes using an established atRA-induced myopia mouse model.

Key Laboratory of Myopia, Eye and ENT Hospital of Fudan University

Male C57BL/6J mice received peribulbar injections of atRA, atRA combined with BMS493 (a pan-RAR inverse agonist), or vehicle every three days for two weeks. Refraction, axial length, vitreous chamber depth, choroidal thickness (ChT), and choroidal blood perfusion (ChBP) were assessed at baseline and endpoint. RNA sequencing was performed on choroid samples, and selected genes were validated by real-time quantitative PCR and Western blot.

BMS493 significantly attenuated atRA-induced myopia in mice. AtRA treatment markedly reduced ChT and ChBP, both of which were notably restored by BMS493. Transcriptome analysis of the choroid identified 265 shared differentially expressed genes with opposite regulation between atRA-treated eyes and atRA+BMS493-treated eyes. Gene Ontology analysis revealed significant enrichment of extracellular matrix (ECM)-related terms in both contrasts. Further, gene set enrichment analysis showed downregulation of ECM gene sets by atRA and upregulation by BMS493. Bone morphogenetic protein 2 (Bmp2) and Bmp7, two myopia-associated ECM genes, were validated at the transcriptional and protein levels, showing regulation consistent with RNA-seq findings.

In mice, atRA induces axial myopia, accompanied by decreased ChT and ChBP. Mechanistically, its choroidal effects are RAR-dependent and associated with ECM modulation.