Funding outcome

We describe our world based on what we see around us, and vision is the sense we most fear losing. Children born blind or who develop early onset retinal dystrophy face immense struggles. Treatment is very limited and although genetic and stem cell therapies provide hope, success depends on an understanding of the mechanism of disease. Here, we propose a revised model of how glial cells support the light-detecting photoreceptors and how failure of that support may underlie a subset of inherited retinal diseases (IRD). Most IRD research so far has focused on intrinsic failure of the photoreceptors or disruption of the adjacent support layer, the retinal pigment epithelium (RPE). In our zebrafish model, we discovered that the primary glial cells of the retina (Muller glia) extend long cellular processes far into the photoreceptor layer. Moreover, these Muller glial long apical processes (MGLAPs) encircle the sensory endings of photoreceptors, contact the RPE, and have highly ordered substructure. We propose exploring the role of MGLAPs in maintaining retinal homeostasis using two disease models. In the first model, we will explore how loss of the glial-specific protein clarin1 disrupts MGLAPs and secondarily impacts photoreceptors. The Human clarin1 (CLRN1) gene is mutated in the type 3A form of Usher Syndrome, a disease of combined hearing and vision loss. Second, we will target the MGLAP-localized protein crumbs 2a (Crb2a) to create a glial model of Leber Congenital Amaurosis, a severe form of retinal dystrophy often caused by mutations in the related CRB1 gene. Finally, we will develop a new method for analysis to enable further study of MGLAPs. In summary, our work will revise the understanding of how Muller glia interact with photoreceptors and support vision.