Transcription factor C/EBPα is required for the development of Ly6C monocytes but not Ly6C monocytes.

Monocytes comprise two major subsets, Ly6C classical monocytes and Ly6C nonclassical monocytes. Notch2 signaling in Ly6C monocytes triggers transition to Ly6C monocytes, which require , , , and . By comparison, less is known about transcriptional requirements for Ly6C monocytes. We find transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) is highly expressed in Ly6C monocytes, but down-regulated in Ly6C monocytes. A few previous studies described the requirement of C/EBPα in the development of neutrophils and eosinophils. However, the role of C/EBPα for in vivo monocyte development has not been understood. We deleted the +37 kb enhancer in mice, eliminating hematopoietic expression of C/EBPα, reproducing the expected neutrophil defect. Surprisingly, we also found a severe and selective loss of Ly6C monocytes, while preserving Ly6C monocytes. We find that BM progenitors from +37 mice rapidly progress through the monocyte progenitor stage to develop directly into Ly6C monocytes even in the absence of Notch2 signaling. These results identify a previously unrecognized role for C/EBPα in maintaining Ly6C monocyte identity.