WNT proteins compose a family of secreted signaling molecules that regulate cell fate and behavior. The possible influence of WNTs on hematopoietic cell fate was examined. Both hematopoietic progenitor cell (HPC)-enriched embryonic avian bone marrow cells and the quail mesodermal stem cell line QCE6 were used for these studies. Under optimized conditions, the bone marrow and QCE6 cells behaved identically and developed into red blood cells (RBCs), monocytes, macrophages, granulocytes, and thrombocytes. This broad range of blood cell phenotypes exhibited by QCE6 cells was dependent on their active expression of WNT11. However, when QCE6 cells were prevented from producing WNT11-by expression of a stably transfected WNT11 antisense transgene-the cultures were dominated by highly vacuolated macrophages. RBCs were absent from these cultures, and the presence of monocytes was greatly diminished. Exposure of these WNT11 antisense cells to soluble WNT11 or WNT5a restored the broad range of blood cell phenotypes exhibited by parental QCE6 cells. Overexpression of WNT protein in QCE6 cells further increased the prevalence of RBCs and monocytes and greatly diminished the appearance of macrophages. Accordingly, treatment of HPC-enriched bone marrow cultures with soluble WNT11 or WNT5a inhibited macrophage formation. Instead, monocytes and RBCs were the prevalent cells displayed by WNT-treated bone marrow cultures. Together, these data indicate that WNTs may play a major role in regulating hematopoietic cell fate.