miR-26 deficiency causes alterations in lens transcriptome and results in adult-onset cataract

Purpose Despite strong evidence demonstrating that normal lens development requires regulation governed by miRNAs, the functional role of specific miRNAs in mammalian lens development remains largely unexplored. Methods A comprehensive analysis of miRNA transcripts in the newborn mouse lens, exploring both differential expression between lens epithelial cells and lens fiber cells and overall miRNA abundance was conducted by miRNA-seq. Mouse lenses lacking each of three abundantly expressed lens miRNAs: miR-184, miR-26 and miR-1 were analyzed to explore the role of these miRNAs in lens development. Results Mice lacking all three copies of miR-26 ( miR-26 TKO ) developed postnatal cataracts as early as 4-6 weeks of age. RNA-seq analysis of neonatal lenses from miR-26 TKO mice exhibited abnormal reduced expression of a cohort of genes found to be lens-enriched and linked to cataract ( e.g. Foxe3 , Hsf4 , Mip , Tdrd7, and numerous crystallin genes), and abnormal elevated expression of genes related to neural development ( Lhx3, Neurod4, Shisa7, Elavl3 ), inflammation ( Ccr1, Tnfrsf12a, Csf2ra) , the complement pathway, and epithelial to mesenchymal transition ( Tnfrsf1a, Ccl7, Stat3, Cntfr ). Conclusion miR-1, miR-184 and miR-26 are each dispensable for normal embryonic lens development. However, loss of miR-26 causes lens transcriptome changes and drives cataract formation.