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. Here, we used deep full-length single-cell RNA-sequencing to distinguish post-mitotic cone and rod developmental states and 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 NRL and THRB RNAs, yet they differentially expressed functionally antagonistic NRL isoforms and prematurely terminated THRB transcripts. Early L/M cone precursors exhibited successive expression of lncRNAs along with MYCN, which composed the seventh most L/M-cone-specific regulon, and SYK, which contributed to the early cone precursors’ proliferative response to RB1 loss. These findings reveal previously unrecognized photoreceptor precursor states and a role for early cone-precursor-intrinsic SYK expression in retinoblastoma initiation.
Photoreceptor-enriched full-length scRNA-seq of developing human retina.
Regulon-defined RPC and photoreceptor precursor states
Differential expression of NRL isoforms in rod and cone precursor populations.
Differential expression of THRB isoforms in rod and cone precursors.
Two post-mitotic photoreceptor precursor populations rapidly expressing rod or cone markers.
An iPRP population with cone-rod properties.
CHRNA1 marks early-born cone and rod precursors.
L/M cone subcluster marker genes, regulons, and pseudotemporal trajectory with successive lncRNA gene expression.
Cone intrinsic MYCN and SYK contribute to the proliferative response to pRB loss.
