Hematopoietic stem cell fate is established by the Notch-Runx pathway
Open accessAbstract
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.
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The zebrafish is a useful model for understanding normal and cancer stem cells.
“The zebrafish is a useful model for understanding normal and cancer stem cells, but analysis has been limited to embryogenesis due to the opacity of the adult fish.”
From Transparent Adult Zebrafish as a Tool for In Vivo Transplantation Analysis (2008) · cites this paper as Burns et al., 2005
The paper’s Abstract describes zebrafish experiments on normal hematopoietic stem-cell specification and maintenance during development and adulthood. It does not establish zebrafish as a model for understanding cancer stem cells; searches for cancer stem cells, leukemia, and tumors found no such discussion in the paper’s body. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPrior work from the authors' laboratory demonstrated that the zebrafish is a useful model for understanding the genetics of hematopoietic stem/progenitor cells and tumor stem cell biology.
“Prior work from our laboratory has demonstrated that the zebrafish is a useful model for understanding the genetics of both HSPC (Burns et al., 2005; Traver et al., 2004a”
From Transparent Adult Zebrafish as a Tool for In Vivo Transplantation Analysis (2008) · cites this paper as Burns et al., 2005
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Wnt proteins are lipid-modified and can act as stem cell growth factors
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Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype
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RUNX1/AML1: A Central Player in Hematopoiesis
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Orkin, S. H., & Zon, L. I. (2008) · Cell · doi:10.1016/j.cell.2008.01.025 · Cited by 2,570 · see citing works
Self-citationTransparent Adult Zebrafish as a Tool for In Vivo Transplantation Analysis
White, R. M., Sessa, A., Burke, C., Bowman, T., LeBlanc, J., Ceol, C., Bourque, C., Dovey, M., Goessling, W., Burns, C. E., et al. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2007.11.002 · Cited by 1,408 · see citing works
Self-citationCorces, M. R., Buenrostro, J. D., Wu, B., Greenside, P. G., Chan, S. M., Koenig, J. L., Snyder, M. P., Pritchard, J. K., Kundaje, A., Greenleaf, W. J., et al. (2016) · Nature Genetics · doi:10.1038/ng.3646 · Cited by 1,151 · see citing works
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Self-citationCanonical Notch Signaling Is Dispensable for the Maintenance of Adult Hematopoietic Stem Cells
Maillard, I., Koch, U., Dumortier, A., Shestova, O., Xu, L., Sai, H., Pross, S. E., Aster, J. C., Bhandoola, A., Radtke, F., et al. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.02.011 · Cited by 317 · see citing works
Stem cells living with a Notch
Koch, U., Lehal, R., & Radtke, F. (2013) · Development · doi:10.1242/dev.080614 · Cited by 283 · see citing works
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Inflammatory signaling regulates hematopoietic stem and progenitor cell development and homeostasis
Collins, A., Mitchell, C. A., & Passegué, E. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201545 · Cited by 111 · see citing works
Imamura, S., Uchiyama, J., Koshimizu, E., Hanai, J.-I., Raftopoulou, C., Murphey, R. D., Bayliss, P. E., Imai, Y., Burns, C. E., Masutomi, K., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003364 · Cited by 58 · see citing works
Self-citation
- Authors
- Burns, C. E., Traver, D., Mayhall, E., Shepard, J. L., & Zon, L. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Zon, Leonard I.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2005-09-15
- Volume
- 19
- Issue
- 19
- Pages
- 2331-2342
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1240042
- OpenAlex
- W2097121011
- Cited by
- 401
- References
- 3
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 13 · 2023: 14 · 2022: 7 · 2021: 13 · 2020: 16 · 2019: 9 · 2018: 23 · 2017: 23 · 2016: 29 · 2015: 27 · 2014: 24 · 2013: 22 · 2012: 25
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American Cancer Society
- National Institutes of Health
- National Heart, Lung, and Blood Institute (5 R01 HL48801-13, R01HL048801)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK067179)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Keywords
- hematopoietic stem cells, Notch signaling, RUNX1, HSC self-renewal, HSC expansion, zebrafish, aorta-gonad-mesonephros, hematopoietic homeostasis, embryonic hematopoiesis
- MeSH terms
- Animals, Aorta, Blood Cells, Cell Differentiation, Gamma Rays, Gonads, Hematopoiesis, Hematopoietic Stem Cells, Homeostasis, Mesonephros, Mutation, Whole-Body Irradiation, Zebrafish, Gene Expression Regulation, Developmental, Cell Lineage, Zebrafish Proteins, Embryonic Development, Core Binding Factor Alpha 2 Subunit
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