Discrete Notch signaling requirements in the specification of hematopoietic stem cells
- Kim, A.D., Melick, C.H., Clements, W.K., Stachura, D.L., Distel, M., Panáková, D., MacRae, C., Mork, L.A., Crump, J.G., Traver, D.
- The EMBO journal 33(20): 2363-73 (Journal)
- Registered Authors
- Clements, Wilson, Crump, Gage DeKoeyer, Distel, Martin, MacRae, Calum A., Panáková, Daniela, Traver, David
- Notch, hematopoietic stem cell, hemogenic endothelium, somite
- MeSH Terms
- Cell Differentiation
- Gene Expression Regulation, Developmental*
- Hematopoietic Stem Cells/cytology
- Hematopoietic Stem Cells/physiology*
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism*
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism*
- Receptor, Notch1/genetics
- Receptor, Notch1/metabolism*
- Receptors, Notch/genetics
- Receptors, Notch/metabolism*
- Signal Transduction
- Wnt Proteins/genetics
- Wnt Proteins/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- 25230933 Full text @ EMBO J.
Kim, A.D., Melick, C.H., Clements, W.K., Stachura, D.L., Distel, M., Panáková, D., MacRae, C., Mork, L.A., Crump, J.G., Traver, D. (2014) Discrete Notch signaling requirements in the specification of hematopoietic stem cells. The EMBO journal. 33(20):2363-73.
Hematopoietic stem cells (HSCs) require multiple molecular inputs for proper specification, including activity of the Notch signaling pathway. A requirement for the Notch1 and dispensability of the Notch2 receptor has been demonstrated in mice, but the role of the remaining Notch receptors has not been investigated. Here, we demonstrate that three of the four Notch receptors are independently required for the specification of HSCs in the zebrafish. The orthologues of the murine Notch1 receptor, Notch1a and Notch1b, are each required intrinsically to fate HSCs, just prior to their emergence from aortic hemogenic endothelium. By contrast, the Notch3 receptor is required earlier within the developing somite to regulate HSC emergence in a non-cell-autonomous manner. Epistatic analyses demonstrate that Notch3 function lies downstream of Wnt16, which is required for HSC specification through its regulation of two Notch ligands, dlc and dld. Collectively, these findings demonstrate for the first time that multiple Notch signaling inputs are required to specify HSCs and that Notch3 performs a novel role within the somite to regulate the neighboring precursors of hemogenic endothelium.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes