title: Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition.
abstract: During development, the hematopoietic lineage transits through hemogenic endothelium, but the signaling pathways effecting this transition are incompletely characterized. Although the Hedgehog (Hh) pathway is hypothesized to play a role in patterning blood formation, early embryonic lethality of mice lacking Hh signaling precludes such analysis. To determine a role for Hh signaling in patterning of hemogenic endothelium, we assessed the effect of altered Hh signaling in differentiating mouse ES cells, cultured mouse embryos, and developing zebrafish embryos. In differentiating mouse ES cells and mouse yolk sac cultures, addition of Indian Hh ligand increased hematopoietic progenitors, whereas chemical inhibition of Hh signaling reduced hematopoietic progenitors without affecting primitive streak mesoderm formation. In the setting of Hh inhibition, induction of either Notch signaling or overexpression of Stem cell leukemia (Scl)/T-cell acute lymphocytic leukemia protein 1 rescued hemogenic vascular-endothelial cadherin(+) cells and hematopoietic progenitor formation. Together, our results reveal that Scl overexpression is sufficient to rescue the developmental defects caused by blocking the Hh and Notch pathways, and inform our understanding of the embryonic endothelial-to-hematopoietic transition.
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Peter Geon
authors.initials: PG
authors.lastname: Kim
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Albacker
authors.forename: Yi-fen
authors.initials: YF
authors.lastname: Lu
authors.forename: Il-ho
authors.initials: IH
authors.lastname: Jang
authors.forename: Yoowon
authors.initials: Y
authors.lastname: Lim
authors.forename: Garrett C
authors.initials: GC
authors.lastname: Heffner
authors.forename: Natasha
authors.initials: N
authors.lastname: Arora
authors.forename: Teresa V
authors.initials: TV
authors.lastname: Bowman
authors.forename: Michelle I
authors.initials: MI
authors.lastname: Lin
authors.forename: M William
authors.initials: MW
authors.lastname: Lensch
authors.forename: Alejandro
authors.initials: A
authors.lastname: De Los Angeles
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: Sabine
authors.initials: S
authors.lastname: Loewer
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D003114:Colony-Forming Units Assay; D004622:Embryo, Mammalian; D004727:Endothelium / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015027:Zebrafish
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053823:Hedgehog Proteins; D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C489366:Tal1 protein, mouse