Date on Master's Thesis/Doctoral Dissertation

12-2013

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Biochemistry and Molecular Biology

Committee Chair

Gregg, Ronald G.

Author's Keywords

Rod bipolar cells; Rod photoreceptors; Retinal dysfunction; Congenital stationary night blindness; CSNB

Subject

Night vision; Vision disorders

Abstract

Glutamate mediated neurotransmission from the rod photoreceptors to rod bipolar cells is critical for vision under low light levels. Disruption of this pathway results in the blinding disorder Congenital Stationary Night Blindness (CSNB), which is hallmarked by the inability to see under dim light. Mouse models of CSNB have been critical to identifying proteins required for glutamate signaling and understanding the mechanism of signaling. Currently, our understanding of rod bipolar signaling is incompletely understood because not all of the protein components of the signalplex have been identified. It was known that the glutamate receptor mGluR6 is coupled to the TRPM1 cation channel, via an unknown G protein mediated mechanism and that regulators of G protein signaling (RGS) are required to terminate signaling. During my graduate work, I identified two new protein components of the rod bipolar cell signalplex that are critical to rod-mediated vision. By mapping the mutation in a novel mouse model of CSNB, I identified Gpr179 as critical to rod bipolar cell signaling. Using immunohistochemistry followed by confocal microscopy and protein interaction assays, I identified GPR179 as a signalplex component. Further, we showed that mutations in GPR179 cause CSNB in humans. I found that GPR179 functions as a hub by interacting with TRPM1 and recruiting the RGS protein complex to the signalplex, which serves to enhance the sensitivity of the system. A report identified mutations in LRIT3 cause CSNB in humans (Zeitz et al., 2013). To determine how LRIT3 contributes to rod vision, I created an Lrit3-/- mouse model of CSNB and found that LRIT3 is required for localizing TRPM1 to the signalplex. These findings add to our understanding of how the visual signal is passed through the retina, and more specifically, rod bipolar cell signalplex architecture, G protein signaling mechanisms, and the causes of CSNB.

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