Combinatorial effects ofFlk1andTal1on vascular and hematopoietic development in the mouse

Abstract

Mouse embryos mutant for the VEGF receptor, VEGFR2, Flk-1, or Kdr, fail to form both endothelial and hematopoietic cells, suggesting a possible role in a common progenitor to both lineages. The transcription factor Tal1 (Scl), is not expressed inFlk1^−/−embryos, consistent with a downstream role in the Flk1 pathway. We tested whether expression ofTal1under theFlk1promoter was sufficient to rescue the loss of endothelial and hematopoietic cells inFlk1mutants. Only partial rescue of hematopoiesis and endothelial development was observed in vivo. However,Flk1^−/Tal1embryonic stem (ES) cells were capable of blast colony formation in vitro at levels equivalent toFlk1^+/−heterozygotes. Ectopic expression ofTal1under theFlk1promoter inFlk1^+/−mouse embryos or ES cells caused no obvious pathology but increased the number of blast colony forming cells (BL-CFCs) and enhanced their hematopoietic potential. These single-cell-derived BL-CFCs also produced smooth muscle cells in vitro. IncreasedTal1expression inhibited smooth muscle differentiation in this assay, whereas loss ofTal1promoted smooth muscle formation. We propose a model in which the combinatorial effects ofFlk1andTal1act to regulate cell fate choice in early development into hematopoietic, endothelial, and smooth muscle lineages.