A genetic screen in zebrafish defines a hierarchical network of pathways required for hematopoietic stem cell emergence
- Burns, C.E., Galloway, J.L., Smith, A.C., Keefe, M.D., Cashman, T.J., Paik, E.J., Mayhall, E.A., Amsterdam, A.H., and Zon, L.I.
- Blood 113(23): 5776-5782 (Journal)
- Registered Authors
- Amsterdam, Adam, Burns (Erter), Caroline, Cashman, Tim, Galloway, Jenna, Keefe, Matthew, Zon, Leonard I.
- MeSH Terms
- Animals, Genetically Modified
- Embryo, Nonmammalian/embryology
- Embryo, Nonmammalian/metabolism
- Gene Expression Regulation, Developmental
- Gene Regulatory Networks/genetics*
- Hematopoietic Stem Cells/cytology*
- Hematopoietic Stem Cells/metabolism*
- Histone Deacetylase 1
- Histone Deacetylases/genetics
- Histone Deacetylases/metabolism
- Receptors, Notch/genetics
- Receptors, Notch/metabolism
- Signal Transduction
- T-Box Domain Proteins/genetics
- T-Box Domain Proteins/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- 19332767 Full text @ Blood
Burns, C.E., Galloway, J.L., Smith, A.C., Keefe, M.D., Cashman, T.J., Paik, E.J., Mayhall, E.A., Amsterdam, A.H., and Zon, L.I. (2009) A genetic screen in zebrafish defines a hierarchical network of pathways required for hematopoietic stem cell emergence. Blood. 113(23):5776-5782.
Defining the genetic pathways essential for hematopoietic stem cell (HSC) development remains a fundamental goal impacting stem cell biology and regenerative medicine. To genetically dissect HSC emergence in the aorta-gonad-mesonephros (AGM) region, we screened a collection of insertional zebrafish mutant lines for expression of the HSC marker, c-myb. Nine essential genes were identified, which were subsequently binned into categories representing their proximity to HSC induction. Using overexpression and loss-of-function studies in zebrafish, we ordered these signaling pathways with respect to each other and to the Vegf, Notch, and Runx programs. Overexpression of vegf and notch are sufficient to induce HSCs in the tbx16 mutant, despite a lack of axial vascular organization. Although embryos deficient for artery specification, such as the phospholipase C gamma-1 (plcgamma1) mutant, fail to specify HSCs, overexpression of notch or runx1 can rescue their hematopoietic defect. The most proximal HSC mutants, like hdac1, were found to have no defect in vessel or artery formation. Further analysis demonstrated that hdac1 acts downstream of Notch signaling but upstream or in parallel to runx1 to promote AGM hematopoiesis. Together, our results establish a hierarchy of signaling programs required and sufficient for HSC emergence in the AGM.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes