Differentiation of the Mononuclear Phagocyte System During Mouse Embryogenesis: The Role of Transcription Factor PU.1

Abstract

During mouse embryogenesis, macrophage-like cells arise first in the yolk sac and are produced subsequently in the liver. The onset of liver hematopoiesis is associated with the transition from primitive to definitive erythrocyte production. This report addresses the hypothesis that a similar transition in phenotype occurs in myelopoiesis. We have used whole mount in situ hybridization to detect macrophage-specific genes expressed during mouse development. The mouse c-fms mRNA, encoding the receptor for macrophage colony-stimulating factor (CSF-1), was expressed on phagocytic cells in the yolk sac and throughout the embryo before the onset of liver hematopoiesis. Similar cells were detected using the mannose receptor, the complement receptor (CR3), or the Microphthalmia transcription factor (MITF) as mRNA markers. By contrast, other markers including the F4/80 antigen, the macrophage scavenger receptor, the S-100 proteins, S100A8 and S100A9, and the secretory product lysozyme appeared later in development and appeared restricted to only a subset of c-fms–positive cells. Two-color immunolabeling on disaggregated cells confirmed that CR3 and c-fmsproteins are expressed on the same cells. Among the genes appearing later in development was the macrophage-restricted transcription factor, PU.1, which has been shown to be required for normal adult myelopoiesis. Mice with null mutations in PU.1 had normal numbers of c-fms–positive phagocytes at 11.5dpc. PU.1(−/−) embryonic stem cells were able to give rise to macrophage-like cells after cultivation in vitro. The results support previous evidence that yolk sac–derived fetal phagocytes are functionally distinct from those arising in the liver and develop via a different pathway.

Expression of Gal4-dependent transgenes in cells of the mononuclear phagocyte system labeled with enhanced cyan fluorescent protein usingCsf1r-Gal4VP16/UAS-ECFP double-transgenic mice

“…1F). This expression pattern closely mimics that of known embryonic macrophage-specific genes: Csf1r and Csf1r-EGFP transgene [7], lysozyme, PU.1, and macrophage mannose receptor [13].…”

Macrophages Promote Osteoblastic Differentiation In Vivo: Implications in Fracture Repair and Bone Homeostasis

“…(21) Indeed the cartilaginous anlage that initiates endochondral ossification is present before macrophage lineage cells develop. (22) However, such cells could play a role in the differentiation or maintenance of certain cell types in bone. Mesenchymal cells play such a role for hematopoietic cells, (23,24) and as such, it is possible that hematopoietic cells also play such a role providing the right niche for mesenchymal cells.…”

Plenary Perspective: The complexity of constitutive and inducible gene expression in mononuclear phagocytes

“…The conclusions of that lineage tracer experiment are very difficult to reconcile with clear evidence that blood-derived monocytes do infiltrate the brain as well as the retina in late gestation and postnatally, engulf dying neurons, and transmogrify into classical microglia [10,11]. The derivation of microglia from yolk sac progenitors was documented well before the recent lineage trace experiments [12,13]. Within the yolk sac, proliferating phagocytic cells arise without any apparent monocyte-like stage.…”