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

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

Author information

1
Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; Howard Hughes Medical Institute, Harvard Stem Cell Institute; Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; Howard Hughes Medical Institute, Harvard Stem Cell Institute; Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; Howard Hughes Medical Institute, Harvard Stem Cell Institute; Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
2
Department of Molecular Cell and Developmental Biology, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095.
3
Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; Howard Hughes Medical Institute, Harvard Stem Cell Institute; Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
4
Division of Pediatric Hematology/Oncology, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305.
5
Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; Howard Hughes Medical Institute, Harvard Stem Cell Institute; Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; Howard Hughes Medical Institute, Harvard Stem Cell Institute; Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; Howard Hughes Medical Institute, Harvard Stem Cell Institute; Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 george.daley@childrens.harvard.edu.

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.

PMID:
25870201
PMCID:
PMC4419355
DOI:
10.1084/jem.20141514
[Indexed for MEDLINE]
Free PMC Article

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