Molecular control of monocyte development

Abstract

Monocyte development is a tightly regulated and multi-staged process, occurring through several defined progenitor cell intermediates. The key transcription factors, including PU.1, IRF8 and KLF4, growth factors, such as M-CSF and IL-34 and cytokines that drive monocyte development from hematopoietic progenitor cells are well defined. However, the molecular controls that direct differentiation into the Ly6C(hi) inflammatory and Ly6C(lo) monocyte subsets are yet to be completely elucidated. This review will provide a summary of the transcriptional regulation of monocyte development. We will also discuss how these molecular controls are also critical for microglial development despite their distinct haematopoetic origins. Furthermore, we will examine recent breakthroughs in defining mechanisms that promote differentiation of specific monocyte subpopulations.

Keywords: IRF8; KLF4; Ly6C(hi) monocytes; Ly6C(lo) monocytes; Microglia; Monocyte development; NR4A1; PU.1; Transcription factors.

Figure 1

The monocyte development pathway. Monocytes are derived from HSC in the bone marrow and spleen via several myeloid-restricted progenitors. Sca-1⁺ HSC (a) give rise to CD34⁺ CMP (b). These cells in turn give rise to CD34⁺CD16/32⁺ GMP (c). A population of these precursors also expresses CD115, CX₃CR1 and Flt-3, known as the MDP (d). A recently identified monocyte precursor downstream of the MDP loses expression of Flt-3 and upregulates Ly6C, known as the cMoP (e). This cell gives rise to Ly6C^hi monocytes (f), which have also been shown to differentiate into Ly6C^lo monocytes (g).