c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish
c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish
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c-Myb 与 Cebp1 并行协同作用来调节斑马鱼中性粒细胞的成熟
DOI：
10.1182/blood-2015-12-686147
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发表时间：
2016-07-21
期刊：
影响因子：
20.3
通讯作者：
Zhang, Yiyue
中科院分区：
文献类型：
--
作者：
Jin, Hao;Huang, Zhibin;Zhang, Yiyue
中性粒细胞是脊椎动物对病原性感染和组织损伤产生先天性免疫的关键效应细胞。已知中性粒细胞发育和功能的失调与各种人类疾病相关。然而，协调中性粒细胞谱系定型、分化和成熟的遗传网络仍然没有完全确定。在这里，我们提出了一个在体内研究，以描绘在斑马鱼胚胎骨髓生成的中性粒细胞的发展的遗传程序。我们发现，c-Myb功能的丧失对巨噬细胞没有影响，但严重损害中性粒细胞的终末分化，导致中性粒细胞与不分叶核和颗粒稀少的积累。这种嗜中性粒细胞缺陷类似于人类中由CCAAT/增强子结合蛋白EBP突变引起的嗜中性粒细胞特异性颗粒缺陷（SGD），至少部分归因于颗粒蛋白转录的下调。同样，Cebp 1（哺乳动物C/EBP β的斑马鱼功能同源物）的遗传失活也导致斑马鱼中类似的SGD样表型。遗传上位性和生化分析进一步揭示了c-Myb和Cebp 1通过直接调节颗粒蛋白基因转录来平行和协同地控制中性粒细胞分化。我们的研究表明，c-MYB是中性粒细胞终末分化的内在主调节因子，也是SGD患者的潜在靶点。
Neutrophils are the key effectors for generating innate immunity in response to pathogenic infection and tissue injury in vertebrates. Dysregulation of neutrophil development and function is known to associate with various human disorders. Yet, the genetic network that orchestrates lineage commitment, differentiation, and maturation of neutrophils remains incompletely defined. Here, we present an in vivo study to delineate the genetic program underlying neutrophil development during zebrafish embryonic myelopoiesis. We show that loss of c-Myb function has no effect on macrophages but severely impairs neutrophil terminal differentiation, resulting in the accumulation of neutrophils with unsegmented nuclei and scant granule. This neutrophilic defect, which resembles the neutrophil-specific granule deficiency (SGD) caused by the mutations in CCAAT/enhancer-binding protein epsilon (C/EBP epsilon) in humans, is attributed, at least in part, to the downregulation of the granule protein transcription. Likewise, genetic inactivation of Cebp1, the zebrafish functional homolog of mammalian C/EBP epsilon, also leads to a similar SGD-like phenotype in zebrafish. Genetic epistasis and biochemical analysis further reveals that c-Myb and Cebp1 act in parallel and cooperatively to control neutrophil differentiation by directly regulating granule protein gene transcription. Our study indicates that c-MYB is an intrinsic master regulator for neutrophil terminal differentiation and a potential target in SGD patients.