Single cell transcriptomics reveals early photoreceptor trajectories and a cancer-predisposed cone precursor state

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 define early photoreceptor developmental states and trajectories that underlie cone-rod differences and identify cone-specific features that contribute to retinoblastoma genesis. The analyses revealed two trajectories from retinal progenitor cells to photoreceptors, one that transitions through a common cone-rod precursor and a second that transitions directly from progenitors to rods. Both L/M cone and rod precursors segregated into early and late maturation states and showed cell type-specific expression of functionally antagonistic NRL and THRB isoforms. Early cone precursor maturation was characterized by successive expression of four lncRNAs along with MYCN and SYK , which contributed to the proliferative response to RB1 loss. These findings reveal previously unrecognized photoreceptor states and trajectories and uncover a role for cone-precursor-intrinsic SYK expression in retinoblastoma initiation. ### Competing Interest Statement The authors have declared no competing interest.