The role of TGF- β signaling in retinal angiogenesis and familial exudative vitreoretinopathy (FEVR)

Abstract

Defects and aberrant retinal angiogenesis lead to a range of rare and common ocular diseases, one of the leading causes of vision loss. FEVR is a rare disease characterized by incomplete retinal angiogenesis with a current genetic diagnosis rate of about 50%. To better understand the disease mechanism of FEVR, we recruited thirteen FEVR probands and identified TGFBR2 as a novel disease gene for FEVR. Experimental evaluation of these variants using human retinal endothelial cells (HREC) indicates they present dominant negative effects by impairing protein expression, localization, and kinase activity. Defective migration capacity, reduced proliferation, and increased apoptosis were observed in human retinal endothelial cells (HRECs) upon the inhibition of TGFBR2. Interestingly, we found that the depletion of TGFBR2 compromised the Norrin/beta-catenin signaling by downregulating its co-receptor TSPAN12 expression, a known disease gene for FEVR. This regulatory effect appears to be driven by the NF-B mediated non-canonical TGF-β signaling. On the other hand, the investigation of the epigenetic landscape found that repression of TGFBR2 triggered widespread chromatin accessibility decrease in enhancers and promoters in HRECs, regardless of whether they were activated, inhibited, or unmediated. This pervasive decrease was controlled by both canonical and non-canonical TGF-β pathways. These less accessible enhancers and promoters presented specific enrichment patterns of transcription factors (TFs). In particular, the promoter region of TSPAN12 presented decreased chromatin accessibility upon TGFBR2 inhibition, which was predicted to be bound to the MAZ, a Zinc Finger Protein TF. Further validation experiments will verify the regulatory role of MAZ on TSPAN12 expression.