Contradictory roles for FGFR signaling in the regulation of hematopoiesis have been reported, with FGFR1 having a positive effect, whereas FGFR2 negatively regulates hematopoiesis in mouse and chick embryogenesis, respectively. We have shown a stage-dependent expression pattern of FGFR1 and FGFR2 during hemangioblast differentiation into primitive hematopoietic cells. Both FGFR1 and FGFR2 are highly expressed in Flk1 + hemangioblasts, and decline in cKit +, CD41 + primitive hematopoietic progenitors. Subsequently FGFR2 gradually increases during further differentiation of hematopoietic cells, while the peak expression of FGFR1 is in CD71 + cells but XAV939 decreases in more differentiated Ter119 + cells. This expression pattern correlates well with the expression of Sprys, in agreement with the concept that FGF/FGFR signaling regulates Sprys expression. Our results suggest that: 1) FGF/FGFR signaling may play a role in mesodermal Flk1 + cell formation and expansion, 2) down-regulation of FGF/FGFR signaling may favor the commitment of Flk1 + to the hematopoietic lineage, 3) FGFR1 may promote the expansion of CD71 + erythroblasts but may not be required for further differentiation and maturation, and 4) FGFR2 may positively regulate erythrocyte differentiation and maturation. Our results also suggest that the feedback circuit between FGFR signaling and Sprys may be necessary for the hematopoietic homeostasis. Further study is required for a better understanding the role of FGF/FGFR signaling in the regulation of primitive hematopoiesis. The Tie2 receptor is expressed in mature endothelial cells, NVP-BKM120 endocardium and in the hemangioblast, a common precursor that gives rise to hematopoietic and endothelial lineages. FACS analysis of pooled normal E8.5 embryo and yolk sac cells showed about 10.3% of Tie2 + cells co-expressing c-Kit, and 2.3% of Tie2 + cells co-expressing CD41 confirming this concept. However, the Myc-tagged Spry1 transgene in Spry1;Tie2-Cre embryos was mainly detected in endothelial and endocardial cells, and only a few CD41 + cells had detectable Myc-tagged Spry1 transgene. Rosa26LacZ reporter staining indicated that Tie2-Cre mediates efficient recombination in our transgenic model. Therefore, it is conceivable that over-expression of Spry1 impairs the survival or viability of CD41 + and CD71 + cells. Indeed, a significant increase in apoptosis occurred in hematopoietic cells of Spry1;Tie2-Cre mice compared to controls. Forced expression of Spry4 in endothelium inhibits endothelial proliferation and vascular morphogenesis. The importance of Spry2 and Spry4 to vascular development was also shown in lossof- function studies where both genes were deleted. Loss of Spry1 leads to abnormal kidney development and is neonatal lethal. In this report, we did not observe a dramatic effect of Spry1 on endothelial cell development by gain- and loss- of function of studies on E9.5 embryos, suggesting that Spry1 has little effect on endothelial cell formation.