Spry1 is expressed in hemangioblasts and negatively regulates primitive hematopoiesis and endothelial cell function |
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Authors: | Yang Xuehui Gong Yan Friesel Robert |
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Institution: | Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, United States of America. |
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Abstract: | BackgroundDevelopment of the hematopoietic and endothelial lineages derives from a common mesodermal precursor, the Flk1+ hemangioblast. However, the signaling pathways that regulate the development of hematopoietic and endothelial cells from this common progenitor cell remains incompletely understood. Using mouse models with a conditional Spry1 transgene, and a Spry1 knockout mouse, we investigated the role of Spry1 in the development of the endothelial and hematopoietic lineages during development.Methodology/Principal FindingsQuantitative RT-PCR analysis demonstrates that Spry1, Spry2, and Spry4 are expressed in Flk1+ hemangioblasts in vivo, and decline significantly in c-Kit+ and CD41+ hematopoietic progenitors, while expression is maintained in developing endothelial cells. Tie2-Cre-mediated over-expression of Spry1 results in embryonic lethality. At E9.5 Spry1;Tie2-Cre embryos show near normal endothelial cell development and vessel patterning but have reduced hematopoiesis. FACS analysis shows a reduction of primitive hematopoietic progenitors and erythroblastic cells in Spry1;Tie2-Cre embryos compared to controls. Colony forming assays confirm the hematopoietic defects in Spry1;Tie2-Cre transgenic embryos. Immunostaining shows a significant reduction of CD41 or CD71 and dpERK co-stained cells in Spry1;Tie2-Cre embryos compared to controls, whereas the number of VEC+ and dpERK co-stained cells is comparable. Compared to controls, Spry1;Tie2-Cre embryos also show a decrease in proliferation and an increase in apoptosis. Furthermore, loss of Spry1 results in an increase of CD41+ and CD71+ cells at E9.5 compared with controls.Conclusions/SignificanceThese data indicate that primitive hematopoietic cells derive from Tie2-expressing hemangioblasts and that Spry1 over expression inhibits primitive hematopoietic progenitor and erythroblastic cell development and expansion while having no obvious effect on endothelial cell development. |
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