Identification and characterization of early human photoreceptor states and cell-state-specific retinoblastoma-related features.

Human cone photoreceptors differ from rods and serve as the retinoblastoma cell-of-origin, yet the developmental basis for their distinct behaviors is poorly understood. Here, we used deep full-length single-cell RNA-sequencing to distinguish post-mitotic cone and rod developmental states and identify cone-specific features that contribute to retinoblastomagenesis. The analyses revealed early post-mitotic cone- and rod-directed populations characterized by higher THRB or NRL regulon activities, an immature photoreceptor precursor population with concurrent cone and rod gene and regulon expression, and distinct early and late cone and rod maturation states distinguished by maturation-associated declines in RAX regulon activity. Unexpectedly, both L/M cone and rod precursors co-expressed and RNAs, yet they differentially expressed functionally antagonistic and isoforms and prematurely terminated transcripts. Early L/M cone precursors exhibited successive expression of several lncRNAs along with , which composed the seventh most L/M-cone-specific regulon, and , which contributed to the early cone precursors' proliferative response to loss. These findings reveal previously unrecognized photoreceptor precursor states and a role for early cone-precursor-intrinsic expression in retinoblastoma initiation.