Thrombin Receptor Regulates Hematopoiesis and Endothelial-to-Hematopoietic Transition
- Authors
- Yue, R., Li, H., Liu, H., Li, Y., Wei, B., Gao, G., Jin, Y., Liu, T., Wei, L., Du, J., and Pei, G.
- ID
- ZDB-PUB-120424-23
- Date
- 2012
- Source
- Developmental Cell 22(5): 1092-1100 (Journal)
- Registered Authors
- Du, Jiu Lin, Jin, Yi
- Keywords
- none
- MeSH Terms
-
- rhoA GTP-Binding Protein/antagonists & inhibitors
- rhoA GTP-Binding Protein/metabolism
- Mice
- Animals
- Hematopoietic Stem Cells/cytology
- Hematopoietic Stem Cells/metabolism*
- Amides/pharmacology
- Cells, Cultured
- Pyrroles/pharmacology
- rho-Associated Kinases/antagonists & inhibitors
- rho-Associated Kinases/metabolism
- Endothelial Cells/cytology
- Endothelial Cells/metabolism*
- Hematopoiesis/physiology*
- Embryonic Stem Cells/cytology
- Embryonic Stem Cells/metabolism
- Zebrafish/blood
- Zebrafish/physiology*
- Pyridines/pharmacology
- Quinazolines/pharmacology
- Receptors, Thrombin/antagonists & inhibitors
- Receptors, Thrombin/genetics
- Receptors, Thrombin/metabolism*
- Cell Differentiation/physiology*
- Flow Cytometry
- PubMed
- 22521721 Full text @ Dev. Cell
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.