How astounding neuronal diversity arises from variable cell lineages in vertebrates remains mostly elusive. By in vivo lineage tracing of ∼1,000 single zebrafish retinal progenitors, we identified a repertoire of subtype-specific stereotyped neurogenic lineages. Remarkably, within these stereotyped lineages, GABAergic amacrine cells were born with photoreceptor cells, whereas glycinergic amacrine cells were born with OFF bipolar cells. More interestingly, post-mitotic differentiation blockage of GABAergic and glycinergic amacrine cells resulted in their respecification into photoreceptor and bipolar cells, respectively, suggesting lineage constraint in cell subtype specification. Using single-cell RNA-seq and ATAC-seq analyses, we further identified lineage-specific progenitors, each defined by specific transcription factors that exhibited characteristic chromatin accessibility dynamics. Finally, single pro-neural factors could specify different neuron types/subtypes in a lineage-dependent manner. Our findings reveal the importance of lineage context in defining neuronal subtypes and provide a demonstration of in vivo lineage-dependent induction of unique retinal neuron subtypes for treatment purposes.

中文翻译：

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不同的谱系环境指导常见的前神经因子来指定不同的视网膜细胞亚型

脊椎动物的可变细胞谱系如何产生令人震惊的神经元多样性，目前仍然难以捉摸。通过对约 1,000 个单个斑马鱼视网膜祖细胞进行体内谱系追踪，我们确定了亚型特异性刻板神经源性谱系的所有组成部分。值得注意的是，在这些定型谱系中，GABA能无长突细胞与感光细胞一起出生，而甘氨酸能无长突细胞与OFF双极细胞一起出生。更有趣的是，GABA能和甘氨酸能无长突细胞的有丝分裂后分化阻断导致它们分别重新特化为光感受器和双极细胞，这表明细胞亚型规范中的谱系限制。使用单细胞 RNA-seq 和 ATAC-seq 分析，我们进一步鉴定了谱系特异性祖细胞，每个祖细胞都由表现出特征性染色质可及性动态的特定转录因子定义。最后，单个亲神经因子可以以谱系依赖的方式指定不同的神经元类型/亚型。我们的研究结果揭示了谱系背景在定义神经元亚型中的重要性，并证明了用于治疗目的的独特视网膜神经元亚型的体内谱系依赖性诱导。