RGC death in a mouse model of congenital glaucoma

Purpose:Mutation in the podosomal adaptor protein SH3PXD2B (nee) causes anterior segment dysgenesis, elevated intraocular pressure (IOP), and congenital glaucoma, as previously described in B10.A-H2h4/(4R)SgDvEg mice. We investigated the effect of the nee mutation in C57BL/6J mice with respect to IOP, total retinal ganglion cell (RGC) death, and RGC subtype specific death in nee mice containing the Trhr-GFP transgene (selectively expresses GFP in ON-OFF direction selective RGCs). Methods:IOP and RGC death were measured in B6.Sh3pxd2bnee mutant (MUT) and wild type (WT) mice at post-natal days 30, 60, 75, and 90. C57BL/6J mice containing the Trhr-GFP transgene were crossed with B6.Sh3pxd2bnee to obtain nee mutant mice expressing GFP in ON-OFF direction selective RGCs. IOP was measured using a TonoLab tonometer. RGC damage was assessed by immunofluorescence of labeled retinal flat mounts using the GFP biomarker and NeuN. Results:Significant IOP elevation was observed in MUT mice at days 30, 60, 75, and 90 compared to WT mice (p2 value of 0.742. Significant differences in the percent cell survival of GFP positive RGCs was observed in MUT mice containing the Trhr-GFPtransgene at 30 days (55.1±15%; n=4-6; p=0.0017), 60 days (16.5±4.6%; n=4-6; p Conclusions:These studies characterized the nee glaucoma phenotype in C57BL/6J mice and demonstrate the specific susceptibility of ON-OFF direction selective RGCs. Future studies will identify susceptibility to additional subtypes of RGCs using this model system. These data are important to determine timing and onset of disease as well as identifying novel therapeutic targets.