¹Centre de Génétique Moléculaire et Cellulaire, Université de Lyon, UMR 5534, Université Claude Bernard Lyon 1, CNRS, Villeurbanne, France

Correspondence: Dr G Mouchiroud, Centre de Génétique Moléculaire et Cellulaire, CNRS Université Lyon 1, UMR 5534, 43 Bd du 11 novembre 1918, Bátiment Gregor Mendel, Villeurbanne 69622, France. E-mail: gmouchir@biomserv.univ-lyon1.fr

²These authors contributed equally to this work

³Current address: The Burnham Institute for Medical Research, Pathology Department, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA

Received 3 January 2007; Revised 3 September 2007; Accepted 14 September 2007; Published online 1 November 2007.

Abstract

Macrophage colony-stimulating factor (M-CSF) has been found to be involved in multiple developmental processes, especially production of cells belonging to the mononuclear phagocyte system. The decision of myeloid progenitor cells to commit to differentiation depends on activation levels of the mitogen-activated protein kinases (MAPK), ERK1 and ERK2. Using the murine myeloid progenitor cell line FD-Fms, we show here that persistent activity of Src-family kinases (SFK) is necessary for FD-Fms cell differentiation to macrophages in response to M-CSF. Chemical inhibition of SFK blocked FD-Fms cell differentiation while it caused strong inhibition of the late phosphorylation of phospholipase C (PLC)-2 and MAPK. The PLC inhibitor U73122, previously shown to block M-CSF-induced differentiation, strongly decreased long-term MAPK phosphorylation. Interestingly, inhibiting SFK with SU6656 or the MAPK kinases MEK with U0126 significantly impaired development of mononuclear phagocytes in cultures of mouse bone marrow cells stimulated with M-CSF. Collectively, results support a model in which SFK are required for sustained PLC activity and MAPK activation above threshold required for commitment of myeloid progenitors to macrophage differentiation.