Asymmetric cell division during T cell development controls downstream fate.
Asymmetric cell division during T cell development controls downstream fate.
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DOI：
10.1083/jcb.201502053
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发表时间：
2015-09-14
期刊：
影响因子：
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通讯作者：
Russell SM
中科院分区：
文献类型：
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作者：
Pham K;Shimoni R;Charnley M;Ludford-Menting MJ;Hawkins ED;Ramsbottom K;Oliaro J;Izon D;Ting SB;Reynolds J;Lythe G;Molina-Paris C;Melichar H;Robey E;Humbert PO;Gu M;Russell SM
T细胞前体在T细胞受体基因组重组后进行不对称细胞分裂，基质细胞线索控制分裂DN 3a T细胞前体的子代对命运决定子Numb和α-Adaptin的差异遗传。在哺乳动物T细胞发育过程中，需要扩增许多单个T细胞克隆，而不仅仅是扩增整个T细胞群，这表明不对称细胞分裂（ACD）可能起作用。我们发现发育中T细胞的ACD通过细胞命运决定因子Numb和α-Adaptin的差异遗传控制细胞命运。ACD特异性地发生在T细胞发育的β-选择阶段，并且随后的分裂主要是对称的。ACD由与基质细胞和趋化因子受体信号传导的相互作用控制，并使用保守的极性调节剂网络。通过删除极性调节因子Scribble或改变命运决定簇的遗传而破坏极性会影响随后的命运决定，从而影响β-选择检查点后产生的DN 4细胞数量。这些发现表明ACD使胸腺微环境能够协调与分化和自我更新相关的命运决定。
T cell precursors undergo asymmetric cell division after T cell receptor genomic recombination, with stromal cell cues controlling the differential inheritance of fate determinants Numb and α-Adaptin by the daughters of a dividing DN3a T cell precursor. During mammalian T cell development, the requirement for expansion of many individual T cell clones, rather than merely expansion of the entire T cell population, suggests a possible role for asymmetric cell division (ACD). We show that ACD of developing T cells controls cell fate through differential inheritance of cell fate determinants Numb and α-Adaptin. ACD occurs specifically during the β-selection stage of T cell development, and subsequent divisions are predominantly symmetric. ACD is controlled by interaction with stromal cells and chemokine receptor signaling and uses a conserved network of polarity regulators. The disruption of polarity by deletion of the polarity regulator, Scribble, or the altered inheritance of fate determinants impacts subsequent fate decisions to influence the numbers of DN4 cells arising after the β-selection checkpoint. These findings indicate that ACD enables the thymic microenvironment to orchestrate fate decisions related to differentiation and self-renewal.