title: Flow-induced protein kinase A-CREB pathway acts via BMP signaling to promote HSC emergence.
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.
authors: 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.
authors: Peter Geon
authors: PG
authors: Kim
authors: 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.
authors: Haruko
authors: H
authors: Nakano
authors: 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.
authors: Partha P
authors: PP
authors: Das
authors: 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.
authors: Michael J
authors: MJ
authors: Chen
authors: 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.
authors: R Grant
authors: RG
authors: Rowe
authors: 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.
authors: Stephanie S
authors: SS
authors: Chou
authors: 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.
authors: Samantha J
authors: SJ
authors: Ross
authors: Division of Pediatric Hematology/Oncology, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305.
authors: Kathleen M
authors: KM
authors: Sakamoto
authors: 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.
authors: Leonard I
authors: LI
authors: Zon
authors: 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.
authors: Thorsten M
authors: TM
authors: Schlaeger
authors: 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.
authors: Stuart H
authors: SH
authors: Orkin
authors: 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.
authors: Atsushi
authors: A
authors: Nakano
authors: 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.
authors: George Q
authors: GQ
authors: Daley
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D008650:Mesonephros / Q000166:cytology / Q000196:embryology; D051379:Mice; D008817:Mice, Mutant Strains; D015398:Signal Transduction / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D017868:Cyclic AMP-Dependent Protein Kinases