Abstract
Two members of the R7 subfamily of regulators of G protein signaling, RGS7 and RGS11, are present at dendritic tips of retinal depolarizing bipolar cells (DBCs). Their involvement in the mGluR6/Gα(o)/TRPM1 pathway that mediates DBC light responses has been implicated. However, previous genetic studies employed an RGS7 mutant mouse that is hypomorphic, and hence the exact role of RGS7 in DBCs remains unclear. We have made a true RGS7-null mouse line with exons 6-8 deleted. The RGS7(-/-) mouse is viable and fertile but smaller in body size. Electroretinogram (ERG) b-wave implicit time in young RGS7(-/-) mice is prolonged at eye opening, but the phenotype disappears at 2 months of age. Expression levels of RGS6 and RGS11 are unchanged in RGS7(-/-) retina, but the Gβ5S level is significantly reduced. By characterizing a complete RGS7 and RGS11 double knock-out (711dKO) mouse line, we found that Gβ5S expression in the retinal outer plexiform layer is eliminated, as is the ERG b-wave. Ultrastructural defects akin to those of Gβ5(-/-) mice are evident in 711dKO mice. In retinas of mice lacking RGS6, RGS7, and RGS11, Gβ5S is undetectable, whereas levels of the photoreceptor-specific Gβ5L remain unchanged. Whereas RGS6 alone sustains a significant amount of Gβ5S expression in retina, the DBC-related defects in Gβ5(-/-) mice are caused solely by a combined loss of RGS7 and RGS11. Our data support the notion that the role of Gβ5 in the retina, and likely in the entire nervous system, is mediated exclusively by R7 RGS proteins.
Highlights
G5Ϫ/Ϫ mice have defective retinal outer plexiform layer and lack b-wave in electroretinogram (ERG)
By characterizing a complete RGS7 and RGS11 double knock-out (711dKO) mouse line, we found that G5S expression in the retinal outer plexiform layer is eliminated, as is the ERG b-wave
To extend the applicability of the finding in depolarizing bipolar cells (DBCs) to other retinal neurons and to address whether G5S can be stabilized in the absence of R7 RGS proteins by other molecules such as canonical G␥ subunits, we generated a triple knock-out mice lacking RGS6, RGS7, and RGS11 in which we found that G5S in the retina is undetectable
Summary
G5Ϫ/Ϫ mice have defective retinal outer plexiform layer and lack b-wave in electroretinogram (ERG). Defective DBCs in RGS7 and RGS11 Double Knock-out Mice importantly, G5 is most likely acting by stabilizing R7 RGS proteins, the possibility that it acts via an RGS-independent mechanism, e.g. through demonstrated interactions with conventional G␥ subunits [6, 11,12,13], has neither been confirmed nor ruled out To address these issues, we have generated the first true RGS7-null mouse line, which resulted in a smaller body size and delayed electroretinogram (ERG) b-waves. By generating a RGS7 and RGS11 double knock-out (711dKO) line, we have recapitulated DBC-related structural and functional defects of G5Ϫ/Ϫ mice in retinal OPL These data demonstrate that G5S works through stabilizing RGS7 and RGS11 in DBC dendrites and that RGS7 alone is as important as RGS11 in the development and function of the first vision synapse. Our data firmly establish that G5S works not as a conventional G subunit, but exclusively through its interaction with R7 RGS proteins
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