Abstract
Purpose :
To define remodeling of photoreceptor synaptic terminals and second-order neurons in canine X-linked progressive retinal atrophy 1 (XLPRA1) caused by a five-nucleotide deletion in RPGR exon ORF15.
Methods :
Retinas of normal and mutant dogs were used for gene expression, western blot and immunohistochemistry. Cell-specific markers were used to examine disease-dependent retinal remodeling.
Results :
In mutant retinas, a number of rod axon terminals retract into the outer nuclear layer (ONL). This neuritic change preceded significant loss of rods, and was evident early in disease. Rod bipolar and horizontal cell processes were found to extend into the ONL, where they appeared to form contacts with the spherules of rod photoreceptors. No ectopic rewiring was observed. As cytoskeletal reorganization was previously shown to underlie photoreceptor axon retraction, we examined normal and mutant retinas for expression of axon guidance receptors ROBO1 and ROBO2, known to regulate actin cytoskeleton dynamics. We found that overall expression of both ROBO1 and ROBO2 is retained at the same level in pre-mature and fully developed normal retinas. However, analysis of pre-disease and early disease retinas identified markedly reduced levels of ROBO1 in rod spherules compared to control. In contrast, no differences in ROBO1 signals were noted in cone pedicles in normal and mutant retinas where ROBO1 levels remained similarly low.
Conclusions :
Depletion of ROBO1 in rod synaptic terminals correlates with the remodeling of axonal and dendritic processes in the outer retina of XLPRA1 dogs, and may play a role in the retraction of rod axons.
This is a 2020 ARVO Annual Meeting abstract.