ZFIN ID: ZDB-PUB-050920-8
Hematopoietic stem cell fate is established by the Notch-Runx pathway
Burns, C.E., Traver, D., Mayhall, E., Shepard, J.L., and Zon, L.I.
Date: 2005
Source: Genes & Development   19(19): 2331-2342 (Journal)
Registered Authors: Burns (Erter), Caroline, Shepard, Jennifer, Traver, David, Zon, Leonard I.
Keywords: Stem cell, Notch, Runx, AGM, zebrafish, irradiation
MeSH Terms:
  • Animals
  • Aorta/cytology
  • Aorta/physiology
  • Blood Cells/cytology
  • Blood Cells/physiology
  • Cell Differentiation/physiology
  • Cell Lineage/physiology*
  • Cell Lineage/radiation effects
  • Core Binding Factor Alpha 2 Subunit/genetics
  • Core Binding Factor Alpha 2 Subunit/metabolism*
  • Embryonic Development/physiology
  • Embryonic Development/radiation effects
  • Gamma Rays
  • Gene Expression Regulation, Developmental/physiology
  • Gene Expression Regulation, Developmental/radiation effects
  • Gonads/cytology
  • Gonads/physiology
  • Hematopoiesis/physiology*
  • Hematopoiesis/radiation effects
  • Hematopoietic Stem Cells/cytology
  • Hematopoietic Stem Cells/metabolism*
  • Homeostasis/physiology
  • Homeostasis/radiation effects
  • Mesonephros/cytology
  • Mesonephros/physiology
  • Mutation
  • Whole-Body Irradiation/methods
  • Zebrafish/anatomy & histology
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 16166372 Full text @ Genes & Dev.
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.