All ETDs from UAB

Advisory Committee Chair

Alecia K Gross

Advisory Committee Members

Marina S Gorbatyuk

Elizabeth S Stzul

John M Parant

Brad K Yoder

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The overall health and maintenance of rod photoreceptors depends on directed vectorial transport of rhodopsin from its synthesis within the inner segment to its target destination the outer segment disk membranes. Numerous proteins are known to be involved in molecular interactions with rhodopsin during transport, including the interaction of nuclear distribution protein C (nudC) with rhodopsin that was first described in Xenopus laevis. We found that the interaction of nudC and rhodopsin is conserved in mammalian retina. This interaction is direct and aberrant expression of nudC results in subcellular localization of rhodopsin. We show for the first time that nudC localizes within the inner segment of photoreceptor cells and is involved in the formation of new disk at the base of the connecting cilium. Expression of the dominant-negative nudCL280P or knockdown of nudC in X. laevis rods leads to impaired disk morphogenesis and progressive retinal degeneration. Strikingly similar phenotypes were observed in our mouse model with rod specific nudC knockout mouse (rodnudC-/-). We found that 3 week and 6 week rodnudC-/- knockout mice have severely reduced electroretinogram (ERG) responses in addition of photoreceptor cell death. Rhodopsin mislocalizes in rodnudC-/- retina and at 6 weeks of age a single nuclei remains in the outer nuclear layer indicating high levels of cell death. Knockout of nudC in mouse rod cells results in dysregulated OS disk formation in both the rodnudC+/- and rodnudC-/- mice. Investigation of actin-modulating protein levels within the retina reveal an increase in F-actin levels in nudC deficient rod cells. In all, this work provides insight for a distinct and novel conserved role nudC plays in rod photoreceptors of the vertebrate retina. The data gathered in these studies will provide insight on rhodopsin trafficking and disk membrane morphogenesis, while also highlighting a previously unknown role for a highly evolutionarily conserved protein.

Share

COinS