title: Endothelial Smad4 restrains the transition to hematopoietic progenitors via suppression of ERK activation.
abstract: In mouse mid-gestational embryos, definitive hematopoietic stem progenitor cells are derived directly from a very small proportion of the arterial endothelium. However, the physiological mechanisms restraining excessive endothelial-hematopoietic transition remain elusive. We show here that genetic deletion of Smad4 from the endothelium stage (using Tie2-Cre), but not from embryonic hematopoietic cells (using Vav-Cre), leads to a strikingly augmented emergence of intra-arterial hematopoietic clusters and an enhanced in vitro generation of hematopoietic progenitors, with no increase in the proliferation and survival of hematopoietic cluster cells. This finding indicates a temporally restricted negative effect of Smad4 on the endothelial to hematopoietic progenitor transition. Furthermore, the absence of endothelial Smad4 causes an increased expression of subaortic bone morphogenetic protein 4 and an activation of aortic extracellular signal-regulated kinase, thereby resulting in the excessive generation of blood cells. Collectively, our data for the first time identify a physiological suppressor that functions specifically during the transition of endothelial cells to hematopoietic progenitors and further suggest that endothelial Smad4 is a crucial modulator of the subaortic microenvironment that controls the hematopoietic fate of the aortic endothelium.
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, China;
authors.forename: Yu
authors.initials: Y
authors.lastname: Lan
authors.forename: Wenyan
authors.initials: W
authors.lastname: He
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Jiao
authors.initials: J
authors.lastname: Gao
authors.forename: Weili
authors.initials: W
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology* / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D015536:Down-Regulation; D004622:Embryo, Mammalian; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051901:Smad4 Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases