PUBLICATION

Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart

Authors
Vermot, J., Forouhar, A.S., Liebling, M., Wu, D., Plummer, D., Gharib, M., and Fraser, S.E.
ID
ZDB-PUB-101027-51
Date
2009
Source
PLoS Biology   7(11): e1000246 (Journal)
Registered Authors
Forouhar, Arian S., Fraser, Scott E., Liebling, Michael, Vermot, Julien
Keywords
Embryos, Blood flow, Heart, Endothelial cells, Gene flow, Heart rate, Cardiac atria, Zebrafish
MeSH Terms
  • Heart Valves/embryology*
  • Kruppel-Like Transcription Factors/genetics
  • Kruppel-Like Transcription Factors/metabolism*
  • Gene Expression Regulation, Developmental/drug effects
  • Gene Expression Regulation, Developmental/genetics
  • Hemodynamics/drug effects
  • Animals
  • In Situ Hybridization
  • Reverse Transcriptase Polymerase Chain Reaction
  • Microscopy, Confocal
  • Embryo, Nonmammalian
  • Blood Circulation/drug effects
  • Blood Circulation/genetics
  • Lidocaine/pharmacology
  • Heart/embryology*
  • Temperature
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
(all 19)
PubMed
19924233 Full text @ PLoS Biol.
Abstract
Heart valve anomalies are some of the most common congenital heart defects, yet neither the genetic nor the epigenetic forces guiding heart valve development are well understood. When functioning normally, mature heart valves prevent intracardiac retrograde blood flow; before valves develop, there is considerable regurgitation, resulting in reversing (or oscillatory) flows between the atrium and ventricle. As reversing flows are particularly strong stimuli to endothelial cells in culture, an attractive hypothesis is that heart valves form as a developmental response to retrograde blood flows through the maturing heart. Here, we exploit the relationship between oscillatory flow and heart rate to manipulate the amount of retrograde flow in the atrioventricular (AV) canal before and during valvulogenesis, and find that this leads to arrested valve growth. Using this manipulation, we determined that klf2a is normally expressed in the valve precursors in response to reversing flows, and is dramatically reduced by treatments that decrease such flows. Experimentally knocking down the expression of this shear-responsive gene with morpholine antisense oligonucleotides (MOs) results in dysfunctional valves. Thus, klf2a expression appears to be necessary for normal valve formation. This, together with its dependence on intracardiac hemodynamic forces, makes klf2a expression an early and reliable indicator of proper valve development. Together, these results demonstrate a critical role for reversing flows during valvulogenesis and show how relatively subtle perturbations of normal hemodynamic patterns can lead to both major alterations in gene expression and severe valve dysgenesis.
Genes / Markers
Figures
Figure Gallery (15 images) / 2
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
s843TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    gata1aMO1-gata1aMRPHLNO
    gata1aMO2-gata1aMRPHLNO
    gata2aMO1-gata2aMRPHLNO
    gjd6MO1-gjd6MRPHLNO
    klf2aMO3-klf2aMRPHLNO
    klf2aMO4-klf2aMRPHLNO
    myh6MO1-myh6MRPHLNO
    1 - 7 of 7
    Show
    Fish
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    1 - 1 of 1
    Show
    Mapping
    No data available