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

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...

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Bibliographic Details
Published in:Genes & development 2005-10, Vol.19 (19), p.2331-2342
Main Authors: Burns, Caroline Erter, Traver, David, Mayhall, Elizabeth, Shepard, Jennifer L, Zon, Leonard I
Format: Article
Language:English
Subjects:
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
Danio rerio
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
Research Papers
Whole-Body Irradiation - methods
Zebrafish - anatomy & histology
Zebrafish - embryology
Zebrafish - genetics
Zebrafish Proteins - genetics
Zebrafish Proteins - metabolism
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.1337005