Canine Retina Has a Primate Fovea-Like Bouquet of Cone Photoreceptors Which Is Affected by Inherited Macular Degenerations

Abstract

Retinal areas of specialization confer vertebrates with the ability to scrutinize corresponding regions of their visual field with greater resolution. A highly specialized area found in haplorhine primates (including humans) is the fovea centralis which is defined by a high density of cone photoreceptors connected individually to interneurons, and retinal ganglion cells (RGCs) that are offset to form a pit lacking retinal capillaries and inner retinal neurons at its center. In dogs, a local increase in RGC density is found in a topographically comparable retinal area defined as the area centralis. While the canine retina is devoid of a foveal pit, no detailed examination of the photoreceptors within the area centralis has been reported. Using both in vivo and ex vivo imaging, we identified a retinal region with a primate fovea-like cone photoreceptor density but without the excavation of the inner retina. Similar anatomical structure observed in rare human subjects has been named fovea-plana. In addition, dogs with mutations in two different genes, that cause macular degeneration in humans, developed earliest disease at the newly-identified canine fovea-like area. Our results challenge the dogma that within the phylogenetic tree of mammals, haplorhine primates with a fovea are the sole lineage in which the retina has a central bouquet of cones. Furthermore, a predilection for naturally-occurring retinal degenerations to alter this cone-enriched area fills the void for a clinically-relevant animal model of human macular degenerations.

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

“…WT dogs show an ONL thickness distribution that peaks in the superior-central retina ( Fig. 2A, Left) except for the small highly cone enriched fovea-like area (33) (Fig. S1 A and B).…”

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

“…2B, right). The band of ONL retention corresponded to the expected location of the cone-rich canine visual streak (25). To quantify the rates of ONL thinning across the retina, 12 NPHP5-mutant eyes were imaged over a range of ages from 7 weeks to 4 years and ONL topographies were sampled at five standardized locations (Fig.…”

“…Taken together with the importance of central macular vision for humans and our recent finding of the existence of a fovea-like region in canine eyes (25), it will be of substantial translational significance to evaluate whether gene augmentation therapy can improve central cone photoreceptor function by correcting the ciliopathy, forming outer segment structures and restoring trafficking of relevant proteins to these newly formed outer segments. Also important will be evaluation of whether reconstituted retinal signals activate higher visual centers in a blindness that overlaps with development.…”

Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells

“…6 A and B). Intravitreal injection of AAV2/2(4YF)-CAG-LiGluR in the area centralis, a region of high RGC density in the canine retina (40), resulted in potent expression in RGCs by 8 wk postinjection ( Fig. 6 C and D).…”