title: Thrombin receptor regulates hematopoiesis and endothelial-to-hematopoietic transition.
abstract: Hematopoietic development and vascular development are closely related physiological processes during vertebrate embryogenesis. Recently, endothelial-to-hematopoietic transition (EHT) was demonstrated to be critical for hematopoietic stem and progenitor cell induction, but its underlying regulatory mechanisms remain poorly understood. Here we show that thrombin receptor (F2r), a protease-activated G protein-coupled receptor required for vascular development, functions as a negative regulator during hematopoietic development. F2r is significantly upregulated during hematopoietic differentiation of mouse embryonic stem cells (mESCs) and zebrafish hematopoietic development. Pharmacological or genetic inhibition of F2r promotes hematopoietic differentiation, whereas F2r overexpression shows opposite effects. Further mechanistic studies reveal that F2r-RhoA/ROCK pathway inhibits EHT in vitro and negatively regulates zebrafish EHT and hematopoietic stem cell induction in vivo. Taken together, this study demonstrates a fundamental role of F2r-RhoA/ROCK pathway in vertebrate hematopoiesis and EHT, as well as an important molecular mechanism coordinating hematopoietic and vascular development.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Yue
authors.forename: Haisen
authors.initials: H
authors.lastname: Li
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Wei
authors.forename: Ge
authors.initials: G
authors.lastname: Gao
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Tingxi
authors.initials: T
authors.lastname: Liu
authors.forename: Liping
authors.initials: L
authors.lastname: Wei
authors.forename: Jiulin
authors.initials: J
authors.lastname: Du
authors.forename: Gang
authors.initials: G
authors.lastname: Pei
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000097:blood / Q000502:physiology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011725:Pyridines; D011758:Pyrroles; D011799:Quinazolines; D018179:Receptors, Thrombin; C108830:Y 27632; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein