Journal
BLOOD
Volume 113, Issue 23, Pages 5776-5782Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-12-193607
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Funding
- National Heart, Lung, and Blood Institute [5 R01 HL48801]
- National Institute of Diabetes and Digestive and Kidney Diseases [1 K01 DK067179]
- National Institutes of Health grant from the National Center for Research Resources [2 R01 RR012589]
- Howard Hughes Medical Institute
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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 is 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 (plc gamma 1) mutant, fail to specify HSCs, overexpression of notch or runx1 can rescue their hematopoietic defect. The most proximal HSC mutants, such as 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. (Blood. 2009; 113: 5776-5782)
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