A Genetic Screen in Zebrafish Defines a Hierarchical Network of Pathways Required for Hematopoietic Stem Cell Emergence

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2009 Apr 1

PMID 19332767

Citations 61

Authors

Caroline E Burns

Jenna L Galloway

Alexandra C H Smith

Matthew D Keefe

Timothy J Cashman

Elizabeth J Paik

Elizabeth A Mayhall

Adam H Amsterdam

Leonard I Zon

Affiliations

Soon will be listed here.

Abstract

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 (plcgamma1) 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.

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