BioProject

Cone and rod photoreceptors in human enable daytime color and nighttime dark vision respectively and abnormality in photoreceptor development results in blindness. More...

Cone and rod photoreceptors in human enable daytime color and nighttime dark vision respectively and abnormality in photoreceptor development results in blindness. However, when and how the two photoreceptors are fate-determined during development is largely unknown. Herein, we established a cell atlas for human photoreceptor development, based on single-cell transcriptomic profiling of engineered human retinal organoids engineered to trace the photoreceptor lineages during developmentto monitor the photoreceptor lineages during development. For the first time, we demonstrated the subtypes of photoreceptor precursors based on unsupervised clustering of single-cell transcriptomesbifurcation of cell fate in the photoreceptor precursors, withwith the conespecific expression of molecular marker gene PDE6H ands for cone precursor and rod marker gene NR2E3 differentially expressed among others precursor. Further dissection of transcriptional segregation of the two precursors uncovered PHLDA1 as an intrinsic regulator intrinsic regulator in the fate bifurcation of of the rod-related gene networksphotoreceptor subtypes. Photoreceptor precursors with decreased PHLDA1 yield more cones while reduced the number of rods. The PHLDA1-mediated modification of cell fate can be directed downstream of IGF1 signaling, and exhibited an inhibitory effect on AKT phosphorylation which was associated with cone differentiation., which directed the downstream effects of IGF1 to promote the rod differentiation. Collectively, our data identified PHLDA1 as a novel regulator of fate determination of photoreceptors at the precursor stage, andour study shed lights on the cellular and molecular mechanisms of human photoreceptor precursor specification, and provided a framework to study mechanisms of cell fate determination of human retinal cells. Overall design: scRNA-seq profiles of retinal organoid from D45, D80, and D120. Less...