In our line of sight: retinal cell types of mice, monkeys and men

Nervous systems in large multicellular organisms employ diverse cell types to integrate sensory inputs and coordinate motor outputs. The evolution of the nervous system from simpler to more complex organisms has resulted in specialization of its constituent cell types. These specialized neuronal and other cell types play very specific roles in highly specialized neural circuits. In the mammalian visual system, for example, the neurons of the retina, which can be grouped into five major classes—photoreceptor, horizontal, bipolar, amacrine and retinal ganglion cells—connect with each other in a stereotyped retinal circuit (Figure 4-2A), yet each of these classes can in turn be further divided into many types (Section 4.15; Box 4-2).

Moreover, the retina is not a uniform monolith across its surface. Notably, at the center of the simian retina resides an area called the fovea, which is specialized for high acuity spatial and color vision. The fovea contributes about half of all input to the primary visual cortex, and the foveola at its center has a high density of cone photoreceptors and lacks retinal ganglion cells and interneuron processes (Section 4.8). Still, the constituent cell types of the fovea have not yet been catalogued, as much of the recent cell type characterization of the retina has been done in mice, which lack foveas. How cell type diversity differs within the primate retina and how it differs and has changed across retinas of different species over evolution remain a mystery; yet, retinal cell type evolution has prompted general models for how the evolution of cell types may proceed (Section 13.15; Figure 13-25).

Peng et al. utilized single-cell RNA sequencing technology (scRNAseq, Box 4-2, Section 14.13) to catalogue the cell types present in the simian (macaque) retina, including in isolated foveas. Comparisons of the fovea and periphery revealed that most of the same cell types are present in each, but in different proportions and with different gene expression patterns (Peng et al., Figures 1, 3, 4). Accordingly, a few cell types are found only in the fovea or periphery (Peng et al., Figures 1, 3). These findings thus suggest a similar, but not identical, cell types “parts list” between the fovea and periphery.

Peng et al. also identified and compared orthologous neuronal types in mouse and macaque retinas. This analysis revealed an intriguing principle: the level of conservation of cell types decreases along the pathway of visual information processing, with conservation of many types of photoreceptors (first-order cells) and second-order interneurons, but great divergence in the types of retinal ganglion cells, the output projection cell class of the retina (Peng et al., Figure 5).

Finally, Peng et al. present preliminary data suggesting conservation of retinal cell types between macaque, marmoset and human and relayed the expression patterns of retinal disease-associated genes in different cell classes (Peng et al., Figures 6, 7). Such data highlight the insight that can result from studying phylogenetically closer species when trying to understand human disease mechanisms.

These findings raise some new questions: What are the functional implications of the differences in cell types and gene expression between fovea and periphery, and between mouse and simian retinas? How is information processed differently in these different circuits? And what genetic mechanisms drove the divergent evolution of retinal ganglion cells between mice and simians? Future studies should also ask whether these principles apply to other sensory systems as well: In what sensory systems do sensory cell types remain conserved while “downstream” cell types (retinal ganglion cells in Peng et al.) diverge? When downstream cell types diversify, how do conserved sensory cell types connect to the appropriate partners without also diversifying? And what stimulus features and/or developmental constraints influence how sensory systems evolve? Addressing such questions will provide insight into the ways in which creatures from all over life’s kingdom adapt to their diverse environments.

Reference

Peng et al. Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina. Cell 176:1222, 2019 Link