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PMID: 16166372 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Hematopoietic stem cell fate is established by the Notch-Runx pathway.

Genes & development ·Vol. 19 ·No. 19 ·2005-10-01 ·Pages 2331-42

Burns CE, Traver D, Mayhall E, Shepard JL, Zon LI

Abstract

Identifying the molecular pathways regulating hematopoietic stem cell (HSC) specification, self-renewal, and expansion remains a fundamental goal of both basic and clinical biology. Here, we analyzed the effects of Notch signaling on HSC number during zebrafish development and adulthood, defining a critical pathway for stem cell specification. The Notch signaling mutant mind bomb displays normal embryonic hematopoiesis but fails to specify adult HSCs. Surprisingly, transient Notch activation during embryogenesis via an inducible transgenic system led to a Runx1-dependent expansion of HSCs in the aorta-gonad-mesonephros (AGM) region. In irradiated adults, Notch activity induced runx1 gene expression and increased multilineage hematopoietic precursor cells approximately threefold in the marrow. This increase was followed by the accelerated recovery of all the mature blood cell lineages. These data define the Notch-Runx pathway as critical for the developmental specification of HSC fate and the subsequent homeostasis of HSC number, thus providing a mechanism for amplifying stem cells in vivo.

MeSH Terms
Animals Aorta/cytology,physiology Blood Cells/cytology,physiology Cell Differentiation/physiology Cell Lineage/physiology,radiation effects Core Binding Factor Alpha 2 Subunit/genetics,metabolism Embryonic Development/physiology,radiation effects Gamma Rays Gene Expression Regulation, Developmental/physiology,radiation effects Gonads/cytology,physiology Hematopoiesis/physiology,radiation effects Hematopoietic Stem Cells/cytology,metabolism Homeostasis/physiology,radiation effects Mesonephros/cytology,physiology Mutation Whole-Body Irradiation/methods Zebrafish/anatomy & histology,embryology,genetics Zebrafish Proteins/genetics,metabolism
Chemicals
Core Binding Factor Alpha 2 Subunit Zebrafish Proteins runx1 protein, zebrafish
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Burns Caroline Erter
Stem Cell Program and Division of Hematology/Oncology Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Traver David
Mayhall Elizabeth
Shepard Jennifer L
Zon Leonard I
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1337005
Published
2005-10-01
Epub
2005-00-15
Pages
2331-42
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC1240042
Subset
IM
Grants
NIDDK NIH HHS · K01 DK067179 · United States
NHLBI NIH HHS · R01 HL048801 · United States
NIDDK NIH HHS · 1 K01 DK067179-01 A1 · United States
NHLBI NIH HHS · 5 R01 HL48801-13 · United States
External Links
PubMed source DOI: 10.1101/gad.1337005 PMC Full Text View journal details
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