Differentiation of the mononuclear phagocyte system during mouse embryogenesis: The role of transcription factor PU.1

During mouse embryogenesis, macrophage-like cells arise first in the yolk s ac and are produced subsequently in the liver. The onset of liver hematopoi esis is associated with the transition from primitive to definitive erythro cyte production. This report addresses the hypothesis that a similar transi tion in phenotype occurs in myelopoiesis. We have used whole mount in situ hybridization to detect macrophage-specific genes expressed during mouse de velopment. The mouse c-fms mRNA, encoding the receptor for macrophage colon y-stimulating factor (CSF-1), was expressed on phagocytic cells in the yolk sac and throughout the embryo before the onset of liver hematopoiesis, Sim ilar cells were detected using the mannose receptor, the complement recepto r (CR3), or the Microphthalmia transcription factor (MITF) as mRNA markers. By contrast, other markers including the F4/80 antigen, the macrophage sca venger receptor, the S-100 proteins, S100A8 and S100A9, and the secretory p roduct lysozyme appeared later in development and appeared restricted to on ly a subset of c-fms-positive cells. Two-color immunolabeling on disaggrega ted cells confirmed that CR3 and c-fms proteins are expressed on the same c ells. Among the genes appearing later in development was the macrophage-res tricted transcription factor, PU.1, which has been shown to be required for normal adult myelopoiesis. Mice with null mutations in PU.1 had normal num bers of c-fms-positive phagocytes at 11.5dpc. PU.1(-/-) embryonic stem cell s were able to give rise to macrophagelike cells after cultivation in vitro . The results support previous evidence that yolk sac-derived fetal phagocy tes are functionally distinct from those arising in the liver and develop v ia a different pathway. (C) 1999 by The American Society of Hematology.