Nonoverlapping functions for Notch1 and Notch3 during murine steady-state thymic lymphopoiesis
Nonoverlapping functions for Notch1 and Notch3 during murine steady-state thymic lymphopoiesis
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DOI：
10.1182/blood-2011-04-346726
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发表时间：
2011-09-01
期刊：
影响因子：
20.3
通讯作者：
Petrie, Howard T.
中科院分区：
文献类型：
--
作者：
Shi, Jianjun;Fallahi, Mohammad;Petrie, Howard T.
Notch 1信号传导对于稳态胸腺淋巴细胞生成是绝对必要的，但是其他Notch受体的作用，以及它们与Notch 1功能的潜在重叠，仍然不清楚。在这里，我们表明，Notch 1，Notch 3的差异表达的祖胸腺细胞，在DN 3祖阶段达到峰值。使用携带基因捕获等位基因的小鼠，我们表明，胸腺细胞结构在Notch 3缺失的情况下略有减少，尽管通过TCR-α β发育的确定序列的进展是正常的，NKT和TCR γ δ细胞的产生也是正常的。Notch 3缺失的深远影响的缺乏不能用基因捕获等位基因的残余功能来解释，因为插入作图表明靶向等位基因不会编码功能性信号传导结构域。我们还表明，虽然Notch 1和Notch 3共表达的一些早期胸腺内祖细胞，相对温和的表型Notch 3缺失后看到的Notch 1的补偿功能，也没有Notch 3功能解释后看到的同样温和的表型Notch 1的条件（胸腺内）删除。我们的研究表明，Notch 1和Notch 3在胸腺细胞分化过程中执行非重叠功能，而Notch 1在淋巴细胞生成过程的早期是绝对必需的，但在后期阶段两种受体都不是必需的。（血。2011;118（9）：2511-2519）
Notch1 signaling is absolutely essential for steady-state thymic lymphopoiesis, but the role of other Notch receptors, and their potential overlap with the function of Notch1, remains unclear. Here we show that like Notch1, Notch3 is differentially expressed by progenitor thymocytes, peaking at the DN3 progenitor stage. Using mice carrying a gene-trapped allele, we show that thymic cellularity is slightly reduced in the absence of Notch3, although progression through the defined sequence of TCR-alpha beta development is normal, as are NKT and TCR gamma delta cell production. The absence of a profound effect from Notch3 deletion is not explained by residual function of the gene-trapped allele because insertion mapping suggests that the targeted allele would not encode functional signaling domains. We also show that although Notch1 and Notch3 are coexpressed on some early intrathymic progenitors, the relatively mild phenotype seen after Notch3 deletion does not result from the compensatory function of Notch1, nor does Notch3 function explain the likewise mild phenotype seen after conditional (intrathymic) deletion of Notch1. Our studies indicate that Notch1 and Notch3 carry out nonoverlapping functions during thymocyte differentiation, and that while Notch1 is absolutely required early in the lymphopoietic process, neither receptor is essential at later stages. (Blood. 2011;118(9):2511-2519)