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Macrophages depend on colony stimulating factor 1 also known as M-CSF for their growth and differentiation, but the requirements for intracellular signals that lead to macrophage differentiation and function remain unclear. M-CSF is known to activate ERK1 and ERK2, but the importance of this signaling pathway in macrophage development is unknown. In these studies, we characterized a novel model of Erk1- Erk2flox-flox Lyz2Cre-Cre mice in which the ERK2 isoform is deleted from macrophages in the background of global ERK1 deficiency. Cultures of M-CSF-stimulated bone marrow precursors from these mice yielded reduced numbers of macrophages. Whereas macrophages developing from M-CSF-stimulated bone marrow of Erk2flox-flox Lyz2Cre-Cre mice showed essentially complete loss of ERK2 expression, the reduced number of macrophages that develop from Erk1- Erk2flox-flox Lyz2Cre-Cre bone marrow show retention of ERK2 expression, indicating selective outgrowth of a small proportion of precursors in which Cre-mediated deletion failed to occur. The bone marrow of Erk1- Erk2flox-flox Lyz2Cre-Cre mice was enriched for CD11b+ myeloid cells, CD11bhi Gr-1hi neutrophils, Lin- c-Kit+ Sca–1+ hematopoietic stem cells, and Lin- c-Kit+ CD34+ CD16-32+ granulocyte-macrophage progenitors. Culture of bone marrow Lin- cells under myeloid-stimulating conditions yielded reduced numbers of monocytes. Collectively, these data indicate that the defect in production of macrophages is not due to a reduced number of progenitors, but rather due to reduced ability of progenitors to proliferate and produce macrophages in response to M-CSF-triggered ERK signaling. Macrophages from Erk1- Erk2flox-flox Lyz2Cre-Cre bone marrow showed reduced induction of M-CSF-regulated genes that depend on the ERK pathway for their expression. These data demonstrate that ERK1-ERK2 play a critical role in driving M-CSF-dependent proliferation of bone marrow progenitors for production of macrophages.

Autor: Edward T. Richardson, Supriya Shukla, Nancy Nagy, W. Henry Boom, Rose C. Beck, Lan Zhou, Gary E. Landreth, Clifford V. Harding



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