State Key Laboratory of Neuroscience, Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
J Cell Biol. 2020 Sep 7;219(9). doi: 10.1083/jcb.202003026.
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.
脊椎动物中神经元多样性如何产生于可变的细胞谱系，这在很大程度上仍是难以捉摸的。通过对大约 1000 个单个斑马鱼视网膜祖细胞的体内谱系追踪，我们鉴定出了一系列具有特定亚型的定型神经发生谱系。值得注意的是，在这些定型谱系中，GABA 能中间神经元与光感受器细胞一起产生，而甘氨酸能中间神经元与 OFF 双极细胞一起产生。更有趣的是，GABA 能和甘氨酸能中间神经元的有丝分裂后分化阻断导致它们分别特化为光感受器和双极细胞，这表明细胞亚型特化中的谱系约束。通过单细胞 RNA-seq 和 ATAC-seq 分析，我们进一步鉴定了谱系特异性祖细胞，每个祖细胞由特定的转录因子定义，这些转录因子表现出特征性的染色质可及性动力学。最后，单个原神经因子可以以谱系依赖性的方式特化不同的神经元类型/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，并为体内谱系依赖性诱导独特视网膜神经元亚型用于治疗目的提供了证据。
