Flow-induced protein kinase A-CREB pathway acts via BMP signaling to promote HSC emergence
| Autor: | Kim, Peter Geon, Nakano, Haruko, Das, Partha P, Chen, Michael J, Rowe, R Grant, Chou, Stephanie S, Ross, Samantha J, Sakamoto, Kathleen M, Zon, Leonard I, Schlaeger, Thorsten M, Orkin, Stuart H, Nakano, Atsushi, Daley, George Q |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
animal structures
Mammalian Immunology Endothelial Cells Hematopoietic Stem Cells Cyclic AMP-Dependent Protein Kinases Medical and Health Sciences Sodium-Calcium Exchanger Mutant Strains Mice Embryo embryonic structures Mesonephros Bone Morphogenetic Proteins Animals Cyclic AMP Response Element-Binding Protein Signal Transduction |
| Zdroj: | The Journal of experimental medicine, vol 212, iss 5 |
| Popis: | Fluid shear stress promotes the emergence of hematopoietic stem cells (HSCs) in the aorta-gonad-mesonephros (AGM) of the developing mouse embryo. We determined that the AGM is enriched for expression of targets of protein kinase A (PKA)-cAMP response element-binding protein (CREB), a pathway activated by fluid shear stress. By analyzing CREB genomic occupancy from chromatin-immunoprecipitation sequencing (ChIP-seq) data, we identified the bone morphogenetic protein (BMP) pathway as a potential regulator of CREB. By chemical modulation of the PKA-CREB and BMP pathways in isolated AGM VE-cadherin(+) cells from mid-gestation embryos, we demonstrate that PKA-CREB regulates hematopoietic engraftment and clonogenicity of hematopoietic progenitors, and is dependent on secreted BMP ligands through the type I BMP receptor. Finally, we observed blunting of this signaling axis using Ncx1-null embryos, which lack a heartbeat and intravascular flow. Collectively, we have identified a novel PKA-CREB-BMP signaling pathway downstream of shear stress that regulates HSC emergence in the AGM via the endothelial-to-hematopoietic transition. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|