Flow-induced protein kinase A-CREB pathway acts via BMP signaling to promote HSC emergence

J Exp Med. 2015 May 4;212(5):633-48. doi: 10.1084/jem.20141514. Epub 2015 Apr 13.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / embryology*
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Mesonephros / cytology
  • Mesonephros / embryology
  • Mice
  • Mice, Mutant Strains
  • Signal Transduction / physiology*
  • Sodium-Calcium Exchanger / genetics
  • Sodium-Calcium Exchanger / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • NCX1 protein, mouse
  • Sodium-Calcium Exchanger
  • Cyclic AMP-Dependent Protein Kinases