The roles of Gbeta5 and R7 RGS protein in vision

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DESCRIPTION (provided by applicant): The role of heterotrimeric G-proteins in human biology is best represented by rhodopsin/transducin signaling in rod phototransduction. Ironically, how other G-proteins subserve mammalian vision outside photoreceptors is poorly understood. This application will start to fill this knowledge gap by elucidating the roles of the fifth Gb subunit (Gb5) and its obligate partners R7 RGS proteins (RGS6, RGS7, RGS9, RGS11) in mouse retina. We have found a multitude of visual defects in Gb5-/- mice which include: 1) delayed phototransduction recovery; 2) abnormal retinal waves and incomplete refinement of retinogeniculate projections during postnatal development; 3) lack of ERG b-wave; 4) reduced starburst amacrine cell (SAC) dendritic field; and 5) disrupted triadic ribbon synapses in retinal outer plexiform layer. We hypothesize that Gb5 works exclusively with R7 RGS proteins in vivo by stabilizing them and that in its absence the signaling state of Gao is abnormally prolonged to cause these visual defects. A multidisciplinary approach with four independent aims will critically examine the pathologic mechanisms of aforementioned Gb5-/- mouse visual defects. Aim-1 will test the exclusivity of the interaction between Gb5 and R7 RGS proteins by examining the level of Gb5 in various tissues of mutant mice with permutated and total loss of the four R7 RGS genes. Aim- 2 will test whether RGS7 and RGS11 expression is required in a cell autonomous manner for normal development and function of depolarizing bipolar cell (DBC). Aim-3 will examine whether normal SAC structure and function requires RGS6 and RGS7 during retinal development. Aim-4 will test whether prolonged Gao signaling retards dendritic development in various retinal cells including DBCs, SACs, and certain retinal ganglion cells (RGCs) and whether it underlies the dendritic defects observed in these retinal neurons in the absence of Gb5. By completing these aims we expect to significantly advance the heterotrimeric G-protein and the vision fields by firmly establishing the roles of Gb5, R7 RGS, and Gao in the visual system.