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

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 (scRNA-seq) to distinguish post-mitotic cone and rod developmental state...

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Main Authors: Dominic WH Shayler, Kevin Stachelek, Linda Cambier, Sunhye Lee, Jinlun Bai, Bhavana Bhat, Mark W Reid, Daniel J Weisenberger, Jennifer G Aparicio, Yeha Kim, Mitali Singh, Maxwell Bay, Matthew E Thornton, Eamon K Doyle, Zachary Fouladian, Stephan G Erberich, Brendan H Grubbs, Michael A Bonaguidi, Cheryl Mae Craft, Hardeep P Singh, David Cobrinik
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2025-08-01
Series:eLife
Subjects:
photoreceptor development
cones
rods
full-length scRNA-seq
transcript isoforms
regulons
Online Access:https://elifesciences.org/articles/101918
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Summary: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 (scRNA-seq) to distinguish post-mitotic cone and rod developmental states and identify cone-specific features related to retinoblastomagenesis. The analyses revealed nascent, immediately post-mitotic cone and rod precursors characterized by higher THRB or NRL regulon activities, immature and maturing cone and rod precursors with concurrent cone- and rod-related gene and regulon expression, and distinct early and late cone and rod maturation states distinguished by maturation-associated declines in RAX regulon activity. Cell-state-specific gene expression features inferred from full-length scRNA-seq were consistent with past 3' scRNA-seq analyses. Beyond the cell state characterizations, full-length scRNA-seq revealed that both L/M cone and rod precursors co-expressed NRL and THRB RNAs yet differentially expressed functionally antagonistic NRL isoforms and prematurely terminated THRB transcripts. Moreover, early L/M cone precursors sequentially expressed several lncRNAs along with MYCN, which composed the seventh most L/M-cone-specific regulon, and SYK, which was implicated in the cone precursors’ proliferative response to RB1 loss. These findings reveal previously unresolved photoreceptor precursor states and suggest a role for early cone-precursor-intrinsic SYK expression in retinoblastoma initiation.
ISSN:2050-084X

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