2. Academic Validation
  3. 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

  • bioRxiv. 2025 Apr 24:2023.02.28.530247. doi: 10.1101/2023.02.28.530247.
Dominic W H Shayler 1 2,  Kevin Stachelek 1 3,  Linda Cambier 1,  Sunhye Lee 1,  Jinlun Bai 1 2,  Bhavana Bhat 1,  Mark W Reid 1,  Daniel J Weisenberger 4 5,  Jennifer G Aparicio 1,  Yeha Kim 1,  Mitali Singh 1,  Maxwell Bay 2,  Matthew E Thornton 6,  Eamon K Doyle 7 8,  Zachary Fouladian 1 2,  Stephan G Erberich 7 8,  Brendan H Grubbs 6,  Michael A Bonaguidi 9,  Cheryl Mae Craft 10 11,  Hardeep P Singh 1 11,  David Cobrinik 1 4 5 11
Affiliations

Affiliations

  • 1 The Vision Center, Department of Surgery, and Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
  • 2 Development, Stem Cell, and Regenerative Medicine Program, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 3 Cancer Biology and Genomics Program, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 4 Department of Cancer Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 5 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 6 Maternal-Fetal Medicine Division of the Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 7 Department of Radiology and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
  • 8 Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 9 Department of Development, Stem Cell, and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 10 Department of Integrative Anatomical Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 11 USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
PMID: 38915659 DOI: 10.1101/2023.02.28.530247
Abstract

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 that contribute to retinoblastomagenesis. The analyses revealed nascent, immediately post-mitotic cone- and rod precursor populations 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 based on full-length scRNA-seq were consistent with past single nucleus 3' RNA-seq analyses. Beyond the cell state characterizations, full-length scRNAseq revealed that both L/M cone and rod precursors co-expressed NRL and THRB RNAs, yet they differentially expressed functionally antagonistic NRL and THRB isoforms and prematurely terminated THRB transcripts. Moreover, early L/M cone precursors exhibited successive expression of 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.

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