CSF-1–induced Src signaling can instruct monocytic lineage choice

Controlled regulation of lineage decisions is imperative for hematopoiesis. Yet, the molecular mechanisms underlying hematopoietic lineage choices are poorly defined. CSF-1, the cytokine acting as the principal regulator of monocyte/macrophage development, has been shown to be able to instruct the lineage choice of uncommitted granulocyte macrophage progenitors towards a monocyte/macrophage fate. However, the intracellular signaling pathways involved are unknown. CSF-1 activates a multitude of signaling pathways resulting in a pleiotropic cellular response. The precise role of individual pathways within this complex and redundant signaling network is dependent on cellular context and not well understood. Here, we addressed which CSF-1-activated pathways are involved in transmitting the lineage-instructive signal in primary bone marrow-derived granulocyte macrophage progenitors. While its loss is compensated for by alternative signaling activation mechanisms, Src family kinase signaling is sufficient to transmit the CSF-1 lineage instructive signal. Moreover, c-Src activity is sufficient to drive macrophage fate, even in non-myeloid cells.