Jin, H., Huang, Z., Chi, Y., Wu, M., Zhou, R., Zhao, L., Xu, J., Zhen, F., Lan, Y., Li, L., Zhang, W., Wen, Z., Zhang, Y. (2016) cMyb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish. Blood. 128(3):415-26.
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 are 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 cMyb 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 C/EBPϵ in human, is attributed, at least in part, to the down-regulation 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 cMyb and Cebp1 act in parallel and cooperatively to control neutrophil differentiation by direct regulating granule protein gene transcription. Our study indicates that cMYB is an intrinsic master regulator for neutrophil terminal differentiation and a potential target in SGD patients.