Friday, May 7, 2021
5/7/2021
PROJECT SUMMARY/ABSTRACT Enhanced S-cone syndrome (ESCS) is an inherited retinal degeneration characterized by an increased number of S-cones, retinal dysplasia, and progressive photoreceptor degeneration leading to early night blindness and loss of visual acuity. The disease is caused by mutations in the rod-fate determining transcription factor NR2E3 in humans and the rd7 mouse model. The disease presentation is highly variable in human and dependent on genetic background in the mouse, demonstrating the existence of genetic modifiers. The mouse model demonstrates that the retinal dysplasia is intimately associated with the occurrence of breaks in the external limiting membrane (ELM), a network of adherens/tight junctions between Müller cell apical processes and photoreceptor inner segments. Fragmentation of the ELM is also observed in other retinal diseases associated with dysplasia, such as Leber's Congenital Amaurosis (LCA) due to mutations in crumbs1 (CRB1) and RP27, and in diabetic retinopathy. We have identified a genetic modifier that prevents the fragmentation of the ELM in both the rd7 mouse and the Nrl ko mouse (RP27) models. This discovery strongly suggests a causative role for the ELM fragmentation in the development of photoreceptor dysplasia and provides a tool with which to establish the mechanisms by which ELM breaks occur, how they lead to retinal dysplasia, and how this affects disease progression. In order to identify these mechanisms we will: 1) Determine the natural history of ELM junction formation and photoreceptor differentiation in wt and the rd7 model using marker analysis of cell junction proteins. 2) Identify the cell types involved in the ELM fragmentation by single cell RNAseq analysis. 3) Determine how the modifier protein alters recruitment of junctional proteins to the cell membrane. 4) Identify the molecular basis of additional genetic modifier strains that we have generated to gain further insight into the NR2E3 disease pathways.
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