The retina is a light-sensitive neural tissue that lines the back of the eye, comprised of retinal cells that are essential for vision. All human retinal cells, subclassed as cone or rod photoreceptors, are generated in the womb. Abnormalities in retinal cell development can cause vision-threating disorders, such as retinal dystrophies and retinoblastoma, an early childhood retina cancer. Interestingly, human cone photoreceptors – but not rod photoreceptors – serve as the cell-of-origin in retinoblastoma. Understanding normal retinal development is critical to improving prevention and treatment of these conditions.

Researchers at the Children’s Hospital Los Angeles aimed to identify and characterize the early development of cone and rod photoreceptors using full-length single-cell RNA sequencing, a method that enables identification of RNA isoforms – alternative versions of gene transcripts that help shape cell identity and function – of around 8,000 genes in each developing retinal cell. This approach offers a more detailed portrait of retinal development than previous methods, allowing precise resolution of cell states and identification of cell-type-specific regulatory networks and transcript isoforms to better understand why cone cells can be susceptible to retinoblastoma development. David Cobrinik, MD, PhD, and colleagues determined that early-stage cone photoreceptors (cone precursors) exhibit transcriptomic features similar to retinoblastoma cells – the cell type that gives rise to retinoblastoma. Cone precursors co-express both cone- and rod-associated genes but preferentially express cone-specific RNA isoforms, mirroring retinoblastoma cells. Notably, cone precursors had high expression of SYK, a protein implicated in cancer biology, which may contribute to retinoblastoma initiation following the loss of the RB1 tumor suppressor gene.

Further analysis identified distinct maturation trajectories among cone and rod precursors, characterized by differences in transcription factor expression and selective expression of RNA isoforms. These findings demonstrate how photoreceptors develop over time and highlight the maturing cone precursor’s intrinsic susceptibility to oncogenic transformation.

Cone-related GNAT2 and rod-related NR2E3 RNA co-expression in human cone precursors.

Overall, this study provides a high-resolution map of human photoreceptor development and uncovers molecular features that may predispose cone precursors to retinoblastoma. These insights could inform future strategies to prevent or treat retinal diseases in children and young adults.

Source – Newswise