FIG 3.
Granulopoiesis and associated transcription factors. Terminal neutrophil maturation is characterized by the sequential formation of the three different neutrophil granules and secretory vesicles as well as nuclear segmentation. Granulopoiesis begins with the development of azurophilic granules in myeloblasts and early promyelocytes and ends after the creation of secretory vesicles in mature, segmented cells. Neutrophil granule formation is hierarchical and dependent upon the timing of constituent protein biosynthesis, while exocytosis occurs in the reverse but ordered sequence. Gene expressions of GATA-1, C/EBP-ζ, AML-1, and c-Myc are imperative for azurophilic granule formation. The creation of specific granules occurs in conjunction with declining AML-1, c-Myc, and CDP concentrations. Reductions in the levels of CDP relieve its repression of C/EBP-ε genes, such as gp91phox, allowing the C/EBP-ε-induced transcription of both C/EBP-δ and specific granule proteins. Once the neutrophil matures into a metamyelocyte, it can no longer proliferate, marking the beginning of terminal neutrophil differentiation. This change results from the inhibition of proliferative genes, AML-1, C/EBP-γ, and CDP, and the emergence of antiproliferative factors such as C/EBP-δ and C/EBP-ζ. The transcription factor C/EBP-ε becomes downregulated as gene expressions for C/EBP-β, C/EBP-δ, and C/EBP-ζ are enhanced to form gelatinase granules.