Abstract
The transcription factors that regulate differentiation into the monocyte subset in bone marrow have not yet been identified. Here we found that the orphan nuclear receptor NR4A1 controlled the differentiation of Ly6C− monocytes. Ly6C− monocytes, which function in a surveillance role in circulation, were absent from Nr4a1−/− mice. Normal numbers of myeloid progenitor cells were present in Nr4a1−/− mice, which indicated that the defect occurred during later stages of monocyte development. The defect was cell intrinsic, as wild-type mice that received bone marrow from Nr4a1−/− mice developed fewer patrolling monocytes than did recipients of wild-type bone marrow. The Ly6C− monocytes remaining in the bone marrow of Nr4a1−/− mice were arrested in S phase of the cell cycle and underwent apoptosis. Thus, NR4A1 functions as a master regulator of the differentiation and survival of 'patrolling' Ly6C− monocytes.
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Acknowledgements
We thank K.A. Hogquist (University of Minnesota) for NR4A1-GFP reporter mice; M. Mack (Klinikum der Universitat Regensburg) for antibody to CCR2 (MC-21); K. Ley and I. Shaked for discussions; and A. Blatchley, D. Yoakum and D. Huynh for assistance with management of the mouse colony. Supported by the US National Institutes of Health (R01 HL071141 and R01 HL079621 to C.C.H.).
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R.N.H. and L.M.C. designed and did experiments, analyzed data and contributed to the writing of the manuscript; H.G.H. did experiments with NR4A1-GFP mice; D.N. and A.M.G. did experiments; J.A.P. conceived of the studies of NR4A1-GFP mice, analyzed data and contributed to the writing of the manuscript; F.G. conceived of and directed the research related to intravital microscopy, analyzed data and contributed to the writing of the manuscript; and C.C.H. conceived of the research, directed the study, assisted with experimental design and contributed to the writing of the manuscript.
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Hanna, R., Carlin, L., Hubbeling, H. et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C− monocytes. Nat Immunol 12, 778–785 (2011). https://doi.org/10.1038/ni.2063
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DOI: https://doi.org/10.1038/ni.2063
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