Biology subjects

Peng, Y.-R.

Publications and source records attributed to Peng, Y.-R..

7 recordsLinked to original sources

bioRxiv2023

Molecular Characterization of the Sea Lamprey Retina Illuminates the Evolutionary Origin of Retinal Cell Types

The lamprey, a primitive jawless vertebrate whose ancestors diverged from all other vertebrates over 500 million years ago, offers a unique window into the primordial formation of the retina. Using single-cell RNA-sequencing, we characterized retinal cell types in lamprey and compared their molecular differentiation and regulatory networks with those in mouse and other jawed vertebrates. Our analysis revealed six cell classes and 74 distinct cell types. We discovered multiple conserved cell types shared between jawless and jawed lineages, including notably rods and cones, ON and OFF bipolar cells, and starburst amacrine cells. The conservation of these cell types indicates their emergence early in vertebrate evolution, highlighting the primal designs of retinal circuits for the rod pathway, ON-OFF discrimination, and direction selectivity. In contrast to this evidence for conservation, the pathways of diversification for amacrine cells and retinal ganglion cells appear to have distinctly diverged between the two lineages. Furthermore, we inferred master regulators in specifying retinal cell classes in both lamprey and macaque and identified common regulatory elements across species, underscoring the ancestral nature of the molecular origins governing retinal cell classes. Altogether, our characterization of the lamprey retina illuminates the evolutionary origin of visual processing in the retina.

evolutionary biology↗

bioRxiv2023

Evolutionary and Developmental Specialization of Foveal Cell Types in the Marmoset

In primates, high-acuity vision is mediated by the fovea, a small specialized central region of the retina. The fovea, unique to the anthropoid lineage among mammals, undergoes notable neuronal morphological changes during postnatal maturation. However, the extent of cellular similarity across anthropoid foveas and the molecular underpinnings of foveal maturation remain unclear. Here, we used high throughput single cell RNA sequencing to profile retinal cells of the common marmoset (Callithrix jacchus), an early divergent in anthropoid evolution from humans, apes, and macaques. We generated atlases of the marmoset fovea and peripheral retina for both neonates and adults. Our comparative analysis revealed that marmosets share almost all its foveal types with both humans and macaques, highlighting a conserved cellular structure among primate foveas. Furthermore, by tracing the developmental trajectory of cell types in the foveal and peripheral retina, we found distinct maturation paths for each. In-depth analysis of gene expression differences demonstrated that cone photoreceptors and Muller glia, among others, show the greatest molecular divergence between these two regions. Utilizing single-cell ATAC-seq and gene-regulatory network inference, we uncovered distinct transcriptional regulations differentiating foveal cones from their peripheral counterparts. Further analysis of predicted ligand-receptor interactions suggested a potential role for Muller glia in supporting the maturation of foveal cones. Together, these results provide valuable insights into foveal development, structure, and evolution. Significance statementThe sharpness of our eyesight hinges on a tiny retinal region known as the fovea. The fovea is pivotal for primate vision and is susceptible to diseases like age-related macular degeneration. We studied the fovea in the marmoset-a primate with ancient evolutionary ties. Our data illustrated the cellular and molecular composition of its fovea across different developmental ages. Our findings highlighted a profound cellular consistency among marmosets, humans, and macaques, emphasizing the value of marmosets in visual research and the study of visual diseases.

neuroscience↗

bioRxiv2023

Evolution of neuronal cell classes and types in the vertebrate retina

The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs (Baden et al., 2020). One might expect that retinal cell types evolved to accommodate these varied needs, but this has not been systematically studied. Here, we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a teleost fish, a bird, a reptile and a lamprey. Molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells [RGCs] and Muller glia) is striking, with transcriptomic differences across species correlated with evolutionary distance. Major subclasses are also conserved, whereas variation among types within classes or subclasses is more pronounced. However, an integrative analysis revealed that numerous types are shared across species based on conserved gene expression programs that likely trace back to the common ancestor of jawed vertebrates. The degree of variation among types increases from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified mammalian orthologs of midget RGCs, which comprise >80% of RGCs in the human retina, subserve high-acuity vision, and were believed to be primate-specific (Berson, 2008); in contrast, the mouse orthologs comprise <2% of mouse RGCs. Projections both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.

neuroscience↗

bioRxiv2021

Diversification of multipotential postmitotic mouse retinal ganglion cell precursors into discrete types

The genesis of broad neuronal classes from multipotential neural progenitor cells has been extensively studied, but less is known about the diversification of a single neuronal class into multiple types. We used single-cell RNA-seq to study how newly-born (postmitotic) mouse retinal ganglion cell (RGC) precursors diversify into ~45 discrete types. Computational analysis provides evidence that RGC type identity is not specified at mitotic exit, but acquired by gradual, asynchronous fate restriction of postmitotic multipotential precursors. Some types are not identifiable until a week after they are generated. Immature RGCs may be specified to project ipsilaterally or contralaterally to the rest of the brain before their type identity has been determined. Optimal transport inference identifies groups of RGC precursors with largely non-overlapping fates, distinguished by selectively expressed transcription factors that could act as fate determinants. Our study provides a framework for investigating the molecular diversification of discrete types within a neuronal class.

neuroscience↗

bioRxiv2020

CELL ATLAS OF THE HUMAN FOVEA AND PERIPHERAL RETINA

Most irreversible blindness results from retinal disease. To advance our understanding of the etiology of blinding diseases, we used single-cell RNA-sequencing (scRNA-seq) to analyze the transcriptomes of [~]85,000 cells from the fovea and peripheral retina of seven adult human donors. Utilizing computational methods, we identified 58 cell types within 6 classes: photoreceptor, horizontal, bipolar, amacrine, retinal ganglion and non-neuronal cells. Nearly all types are shared between the two retinal regions, but there are notable differences in gene expression and proportions between foveal and peripheral cohorts of shared types. We then used the human retinal atlas to map expression of 636 genes implicated as causes of or risk factors for blinding diseases. Many are expressed in striking cell class-, type-, or region-specific patterns. Finally, we compared gene expression signatures of cell types between human and the cynomolgus macaque monkey, Macaca fascicularis. We show that over 90% of human types correspond transcriptomically to those previously identified in macaque, and that expression of disease-related genes is largely conserved between the two species. These results validate the use of the macaque for modeling blinding disease, and provide a foundation for investigating molecular mechanisms underlying visual processing.

neuroscience↗

bioRxiv2020

Cell Atlas of Aqueous Humor Outflow Pathways in Eyes of Humans and Four Model Species Provides Insights into Glaucoma Pathogenesis

Increased intraocular pressure (IOP) represents a major risk factor for glaucoma, a prevalent eye disease characterized by death of retinal ganglion cells that carry information from the eye to the brain; lowering IOP is the only proven treatment strategy to delay disease progression. The main determinant of IOP is the equilibrium between production and drainage of aqueous humor, with compromised drainage generally viewed as the primary contributor to dangerous IOP elevations. Drainage occurs through two pathways in the anterior segment of the eye, called conventional and uveoscleral. To gain insights into the cell types that comprise these pathways, we used high-throughput single cell RNA sequencing (scRNA-seq). From [~]24,000 single cell transcriptomes, we identified 19 cell types with molecular markers for each and used histological methods to localize each type. We then performed similar analyses on four organisms used for experimental studies of IOP dynamics and glaucoma: cynomolgus macaque (Macaca fascicularis), rhesus macaque (Macaca mulatta), pig (Sus scrofa) and mouse (Mus musculus). Many human cell types had counterparts in these models, but differences in cell types and gene expression were evident. Finally, we identified the cell types that express genes implicated in glaucoma in all five species. Together, our results provide foundations for investigating the pathogenesis of glaucoma, and for using model systems to assess mechanisms and potential interventions.

cell biology↗

bioRxiv2018

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina

High acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible model organisms lack a fovea, its specialized function and dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate and validate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >65 cell types match between the two regions, but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved, but that projection neuron types and programs diverge, despite conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 6 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

neuroscience↗