Structure of cone photoreceptors

Abstract

Although outnumbered more than 20:1 by rod photoreceptors, cone cells in the human retina mediate daylight vision and are critical for visual acuity and color discrimination. A variety of human diseases are characterized by a progressive loss of cone photoreceptors but the low abundance of cones and the absence of a macula in non-primate mammalian retinas have made it difficult to investigate cones directly. Conventional rodents (laboratory mice and rats) are nocturnal rod-dominated species with few cones in the retina, and studying other animals with cone-rich retinas presents various logistic and technical difficulties. Originating in the early 1900s, past research has begun to provide insights into cone ultrastructure but has yet to afford an overall perspective of cone cell organization. This review summarizes our past progress and focuses on the recent introduction of special mammalian models (transgenic mice and diurnal rats rich in cones) that together with new investigative techniques such as atomic force microscopy and cryo-electron tomography promise to reveal a more unified concept of cone photoreceptor organization and its role in retinal diseases.

Figure 1

Differences in photoreceptors and their arrangement in the retina. Rod and cone photoreceptors are displayed in a cross-sectional depiction of the retina also showing connections of these photoreceptors to retinal pigment epithelium distally and relaying cells (bipolar, horizontal, amacrine, ganglion) proximally. Electron microscopic images are shown of a ROS (A) and a COS (image provided by Dr. Steven K. Fisher) (B). The rod structure has a longer outer segment with discs packed without connections to the ciliary membrane, in stark contrast to the COS discs that are continuously connected by the ciliary membrane.

Figure 2

Distribution of photoreceptors in the eye. Overall, rods outnumber cones by a ratio of 20:1 or greater in the retina. However, in the fovea, the cone density is the highest and is correlated with visual acuity.

Figure 3

Structure and renewal of rod and cone discs. Discs in the cone photoreceptor (A) are not unique evaginations completely separated from the cilium membrane, but instead retain connection to the cilium that extends the entire length of the outer segment. Early EM data indicated that discs of the COS feature partial folds composed of BE and DI. The arrow indicating growth away from the ciliary stalk represents a BE showing a developing COS surrounded by new membrane whereas arrows pointing toward the ciliary stalk represent more DI forming new but shorter COS. More recent work has shown that this representation is not a unifying model and the disc morphogeneis is more dependent on incomplete rim protein (perpherin/rds) formation. Regardless of the mechanism, the continuous membrane structure of cone discs permits an increased surface area that could explain a phototransduction cascade distinct from rod cells. (B) The cone axoneme (shown in red) extends the length of the cone ciliary stalk, indicating its importance in disc morphogenesis and turnover. The rod photoreceptor (C) features individualized discs that do not maintain any connection to the rod cilium. Furthermore, the ciliary axoneme (shown in red) does not extend the entire length of the ROS.

Figure 4

Homology model of S-cone (blue) opsin. (A) The S-cone opsin (pdb id: 1kpn) is shown in blue with the retinal chromophore shown as red sticks and Tyr262 side chain colored by atom. The shown opsin model is a homology based structure from bovine rhodopsin generated with the program Modeler in the Insight II package. The only obvious differences between the two lie in the N- and C-terminal regions, with differences between the blue opsin and rhodopsin being minimal. Homology modeling of the other cone pigment opsins also revealed very similar differences. (B) The modeled retinal binding site is shown with the retina depicted as red sticks and blue opsin residues as sticks colored by atom. The major difference seen between the three pigments is that, unlike the red and green opsins where the central residue forming the retinal cavity is Trp281 (analogous to Trp265 in bovine rhodopsin), the central residue forming the cavity in blue cone pigment is Tyr262 and there is no Glu residue to act as a counter ion to the chromophore Schiff base, resulting in the blue shift of this opsin.

Figure 5

Evolution of photoreceptors. This retinal model is based on the ferret, a mammal with a developmentally immature retina at birth. (A) Cones and rods have indistinct morphologies at birth with both photoreceptors extending processes to the inner plexiform layer (IPL). (B) At 2 weeks of age, morphologies are still indistinct but their processes retract and contact horizontal and bipolar cells. (C) Finally at 4 weeks or age, cones and rods are morphologically distinct with discernable inner and outer segments.

Figure 6

Model for transcriptional control of photoreceptor development. Different transcriptional factors that control rod and cone cell differentiation are indicated. Crx activation is required for both rod and cone development, but is not essential for photoreceptor differentiation. Both Nrl and Nr2e3 are essential. Nrl activates rod specific transcripts and inhibits cone specific transcripts and also activates Nr2e3, which in turn amplifies the effect of Nrl by inhibiting cone specific transcripts. Nr2e3 is also a physiological target of the transcriptional co-regulator Pias3. SUMOylation by Pias3 directs the action of Nr2e3 as a promoter of rod genesis and suppression of cone pathways. TR-β2 and RXRγ are downstream of these transcription factors in the cone pathway that take committed cone progenitors and modulate S versus M/L cone opsin maturation.