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Glaucoma is characterized by a progressive degeneration of retinal ganglion cells (RGCs), leading to irreversible vision loss. Currently, there is no effective treatment for RGC degeneration. We used a disease‐in‐a‐dish stem cell model to examine the developmental susceptibility of RGCs to glaucomatous degeneration, which may inform on the formulation of therapeutic approaches. Here, we used single‐cell transcriptome analysis of  SIX6  risk allele ( SIX6   risk allele  ) primary open angle glaucoma patient‐specific and control hRGCs to compare developmental trajectories in terms of lineage‐ and stage‐specific transcriptional signature to identify dysregulated stages/genes, and subtype composition to estimate the relative vulnerability of RGCs to degeneration because their ability to regenerate axons are subtype‐specific. The developmental trajectories, beginning from neural stem cells to RGCs, were similar between  SIX6   risk allele   and control RGCs. However, the differentiation of  SIX6   risk allele   RGCs was relatively stalled at the retinal progenitor cell stage, compromising the acquisition of mature phenotype and subtype composition, compared with controls, which was likely due to dysregulated mTOR and Notch signaling pathways. Furthermore,  SIX6   risk allele   RGCs, as compared with controls, expressed fewer genes corresponding to RGC subtypes that are preferentially resistant to degeneration. The immature phenotype of  SIX6   risk allele   RGCs with underrepresented degeneration‐resistant subtypes may make them vulnerable to glaucomatous degeneration.

Mapping developmental trajectories and subtype diversity of normal and glaucomatous human retinal ganglion cells by single‐cell transcriptome analysis