Essential control of early B-cell development by Mef2 transcription factors
Essential control of early B-cell development by Mef2 transcription factors
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DOI：
10.1182/blood-2015-04-643270
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发表时间：
2016-02-04
期刊：
影响因子：
20.3
通讯作者：
Stocking, Carol
中科院分区：
文献类型：
--
作者：
Herglotz, Julia;Unrau, Ludmilla;Stocking, Carol
不同发育基因网络的顺序激活控制着细胞的最终身份，但启动下游程序所涉及的机制尚不完全清楚。前 B 细胞受体 (pre-BCR) 是 B 细胞发育的重要检查点，对于前 B 细胞转变为未成熟 B 细胞至关重要。在这里，我们表明前 BCR 激活肌细胞增强因子 2 (Mef2) 转录因子 (TF) 对于启动后续遗传网络是必要的。我们证明，在缺乏 Mef2c 和 Mef2d TF 的小鼠中，B 细胞发育在前 B 细胞阶段被阻断，并且前 BCR 信号通过 Erk5 丝裂原激活激酶的磷酸化增强了 Mef2c/d 的转录活性。这种激活有助于诱导 Kruppel 样因子 2 以及 AP1 和 Egr 家族的几个直接早期基因。最后，我们证明 Mef2 蛋白与其靶基因（Irf4 和 Egr2）的产物协同诱导转录调控的次级波。我们的研究结果揭示了 Mef2c/d 在协调促进早期 B 细胞发育的转录网络中的新作用。
The sequential activation of distinct developmental gene networks governs the ultimate identity of a cell, but the mechanisms involved in initiating downstream programs are incompletely understood. The pre-B-cell receptor (pre-BCR) is an important checkpoint of B-cell development and is essential for a pre-B cell to traverse into an immature B cell. Here, we show that activation of myocyte enhancer factor 2 (Mef2) transcription factors (TFs) by the pre-BCR is necessary for initiating the subsequent genetic network. We demonstrate that B-cell development is blocked at the pre-B-cell stage in mice deficient for Mef2c and Mef2d TFs and that pre-BCR signaling enhances the transcriptional activity of Mef2c/d through phosphorylation by the Erk5 mitogen-activating kinase. This activation is instrumental in inducing Kruppel-like factor 2 and several immediate early genes of the AP1 and Egr family. Finally, we show that Mef2 proteins cooperate with the products of their target genes (Irf4 and Egr2) to induce secondary waves of transcriptional regulation. Our findings uncover a novel role for Mef2c/d in coordinating the transcriptional network that promotes early B-cell development.