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ZIRC
ZFIN ID: ZDB-PUB-110823-3
A blood flow-dependent klf2a-NO signalling cascade is required for stabilization of hematopoietic stem cell programming in zebrafish embryos
Wang, L., Zhang, P., Wei, Y., Gao, Y., Patient, R., and Liu, F.
Date: 2011
Source: Blood   118(15): 4102-10 (Journal)
Registered Authors: Gao, Ya, Liu, Feng, Patient, Roger K., Wang, Lu, Wei, Yonglong, Zhang, Panpan
Keywords: none
MeSH Terms:
  • Animals
  • Blood Flow Velocity/drug effects
  • Blood Flow Velocity/physiology
  • Gene Expression Regulation, Developmental/drug effects
  • Gene Expression Regulation, Developmental/physiology
  • Gene Expression Regulation, Enzymologic/drug effects
  • Gene Expression Regulation, Enzymologic/physiology
  • Gene Knockdown Techniques
  • Hematopoietic Stem Cells/cytology
  • Hematopoietic Stem Cells/metabolism*
  • Kruppel-Like Transcription Factors/genetics
  • Kruppel-Like Transcription Factors/metabolism*
  • Nitric Oxide/genetics
  • Nitric Oxide/metabolism*
  • Nitric Oxide Donors/pharmacology
  • Nitric Oxide Synthase/biosynthesis
  • Nitric Oxide Synthase/genetics
  • Promoter Regions, Genetic/physiology
  • S-Nitroso-N-Acetylpenicillamine/pharmacology
  • Signal Transduction/physiology*
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 21849483 Full text @ Blood
FIGURES
ABSTRACT

Blood flow has long been thought to be important for vessel development and function, but its role in hematopoietic stem cell (HSC) development is not yet fully understood. Here, we take advantage of zebrafish embryos with circulation defects that retain relatively normal early development to illustrate the combinatorial roles of genetic and hemodynamic forces in HSC development. We show that blood flow is not required for initiation of HSC gene expression, but instead is indispensable for its maintenance. Knockdown of klf2a mimics the silent heart (sih/tnnt2a) phenotype while overexpression of klf2a in tnnt2a morphant embryos can rescue HSC defects, suggesting that klf2a is a downstream mediator of blood flow. Furthermore, the expression of nitric oxide (NO) synthase (nos) was reduced in klf2a knockdown embryos, and chromatin immunoprecipitation (ChIP) analysis showed that endogenous Klf2a is bound to the promoters of nos genes in vivo, indicating direct gene regulation. Finally, administration of the NO agonist SNAP can restore HSC development in tnnt2a- and klf2a morphants, suggesting that NO signalling is downstream of Klf2a which is induced by hemodynamic forces. Taken together, we have demonstrated that blood flow is essential for HSC development and is mediated by a klf2a-NO signalling cascade in zebrafish.

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