Myelin regulatory factor(Myrf) is a critical early regulator of retinal pigment epithelial development

Abstract

ABSTRACTMyelin regulatory factor (Myrf) is a critical transcription factor in early retinal and retinal pigment epithelial development, and human variants inMYRFare a cause for nanophthalmos. Single cell RNA sequencing (scRNAseq) was performed onMyrfconditional knockout mice (Rx>Cre Myrffl/fl) at 3 developmental timepoints.Myrfwas expressed specifically in the RPE, and expression was abrogated inRx>Cre Myrffl/fleyes. scRNAseq analysis revealed a loss of RPE cells at all timepoints resulting from cell death. GO-term analysis in the RPE revealed downregulation of melanogenesis and anatomic structure morphogenesis pathways, which were supported by electron microscopy and histologic analysis. Novel structural target genes includingErmnandUpk3b, along with macular degeneration and inherited retinal disease genes were identified as downregulated, and a strong upregulation of TGFß/BMP signaling and effectors was observed. Regulon analysis placedMyrfdownstream ofPax6andMitfand upstream ofSox10in RPE differentiation. Together, these results suggest a strong role for Myrf in the RPE maturation by regulating melanogenesis, cell survival, and cell structure, in part acting through suppression of TGFß signaling and activation ofSox10.SUMMARY STATEMENTMyrfregulates RPE development, melanogenesis, and is important for cell structure and survival, in part through regulation ofErmn,Upk3bandSox10,and BMP/TGFb signaling.