Heilman Shea A, Schriever Hannah C, Kostka Dennis, Koenig Kristen M, Gross Jeffrey M
Department of Ophthalmology, The Louis J. Fox Center for Vision Restoration, The McGowan Institute for Regenerative Medicine, The University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Computational Biology, The University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Sci Rep. 2025 Mar 26;15(1):10404. doi: 10.1038/s41598-025-93825-5.
Tet family methylcytosine dioxygenases recognize and oxidize 5-methyl-cytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Previous work demonstrated the requirement for Tet and 5hmC during zebrafish retinogenesis. tet2;tet3 mutants possessed defects in the formation of differentiated retinal neurons, but the mechanisms underlying these defects are unknown. Here, we leveraged scRNAseq technologies to better understand cell type-specific deficits and molecular signatures underlying the tet2;tet3 retinal phenotype. Our results identified defects in tet2;tet3 retinae that included delayed specification of several retinal cell types, reduced maturity across late-stage cones, expansions of immature subpopulations of horizontal and bipolar cells, and altered biases of bipolar cell subtype fates at late differentiation stages. Together, these data highlight the critical role that tet2 and tet3 play as regulators of cell fate specification and terminal differentiation events during retinal development.
Tet家族甲基胞嘧啶双加氧酶可识别5-甲基胞嘧啶（5mC）并将其氧化为5-羟甲基胞嘧啶（5hmC）。先前的研究表明，斑马鱼视网膜发育过程中需要Tet和5hmC。tet2；tet3突变体在分化的视网膜神经元形成过程中存在缺陷，但这些缺陷背后的机制尚不清楚。在这里，我们利用单细胞RNA测序技术，以更好地了解tet2；tet3视网膜表型背后的细胞类型特异性缺陷和分子特征。我们的结果确定了tet2；tet3视网膜中的缺陷，包括几种视网膜细胞类型的指定延迟、晚期视锥细胞成熟度降低、水平细胞和双极细胞未成熟亚群的扩张，以及双极细胞亚型命运在晚期分化阶段的偏差改变。总之，这些数据突出了tet2和tet3在视网膜发育过程中作为细胞命运指定和终末分化事件调节因子所起的关键作用。
