c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish

• Published in: Blood Vol. 128; no. 3; pp. 415 - 426
• Main Authors: Jin, Hao, Huang, Zhibin, Chi, Yali, Wu, Mei, Zhou, Riyang, Zhao, Lingfeng, Xu, Jin, Zhen, Fenghua, Lan, Yahui, Li, Li, Zhang, Wenqing, Wen, Zilong, Zhang, Yiyue
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-07-2016
• Subjects: Animals; Animals, Genetically Modified; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Cell Differentiation - physiology; Neutrophils - cytology; Neutrophils - metabolism; Proto-Oncogene Proteins c-myb - genetics; Proto-Oncogene Proteins c-myb - metabolism; Zebrafish - genetics; Zebrafish - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-12-686147

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 ε (C/EBPε) 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/EBPε, 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.
•c-Myb is essential for neutrophil terminal differentiation by targeting granule gene expression.•c-Myb and Cebp1 act cooperatively to regulate neutrophil maturation in zebrafish.