PUBLICATION

nkx genes establish SHF cardiomyocyte progenitors at the arterial pole and pattern the venous pole through Isl1 repression

Authors
Colombo, S., de Sena-Tomás, C., George, V., Werdich, A.A., Kapur, S., MacRae, C.A., Targoff, K.L.
ID
ZDB-PUB-180124-10
Date
2017
Source
Development (Cambridge, England)   145(3): (Journal)
Registered Authors
Colombo, Sophie, George, Vanessa, MacRae, Calum A., Targoff, Kimara
Keywords
Arterial pole, Second heart field, Venous pole, Zebrafish, nkx2.5, nkx2.7
MeSH Terms
  • Mutation
  • Homeobox Protein Nkx-2.5/genetics*
  • Humans
  • Body Patterning/genetics
  • Animals, Genetically Modified
  • Myoblasts, Cardiac/cytology*
  • Myoblasts, Cardiac/metabolism*
  • Animals
  • Zebrafish Proteins/genetics*
  • Heart/embryology*
  • Cell Proliferation
  • Heart Defects, Congenital/embryology
  • Heart Defects, Congenital/genetics
  • LIM-Homeodomain Proteins/genetics*
  • Cell Differentiation
  • Transcription Factors/genetics*
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins/genetics*
(all 18)
PubMed
29361575 Full text @ Development
Abstract
NKX2-5 is the most commonly mutated gene associated with human congenital heart defects (CHDs), with a predilection for cardiac pole abnormalities. This homeodomain transcription factor is a central regulator of cardiac development and is expressed in both the first and second heart fields (FHF and SHF). We have previously revealed essential functions of nkx2.5 and nkx2.7, two Nkx2-5 homologs expressed in zebrafish cardiomyocytes, in maintaining ventricular identity. However, the differential roles of these genes in the specific subpopulations of the anterior (aSHF) and posterior (pSHF) SHFs have yet to be fully defined. Here, we show that Nkx genes regulate aSHF and pSHF progenitors through independent mechanisms. We demonstrate that Nkx genes restrict proliferation of aSHF progenitors in the outflow tract, delimit the number of pSHF progenitors at the venous pole and pattern the sinoatrial node acting through Isl1 repression. Moreover, optical mapping highlights the requirement for Nkx gene dose in establishing electrophysiological chamber identity and in integrating the physiological connectivity of FHF and SHF cardiomyocytes. Ultimately, our results may shed light on the discrete errors responsible for NKX2-5-dependent human CHDs of the cardiac outflow and inflow tracts.
Genes / Markers
Figures
Figure Gallery (10 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WT + MO2-isl1astandard conditionsLong-pec
fcu1Tgheat shockPrim-5
fcu1Tgheat shockLong-pec
nkx2.5vu179/vu179standard conditionsPrim-5
nkx2.5vu179/vu179standard conditionsPrim-5
nkx2.5vu179/vu179standard conditionsPrim-5
nkx2.5vu179/vu179standard conditionsLong-pec
nkx2.5vu179/vu179standard conditionsLong-pec
nkx2.5vu179/vu179standard conditionsLong-pec
nkx2.5vu179/vu179standard conditionsLong-pec
1 - 10 of 111
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
f2TgTransgenic Insertion
    fb7TgTransgenic Insertion
      fcu1TgTransgenic Insertion
        twu277TgTransgenic Insertion
          vu179
            		Point Mutation
            vu413
              		Point Mutation
              1 - 6 of 6
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              Human Disease / Model
              Human Disease Fish Conditions Evidence
              congenital heart diseasenkx2.5vu179/vu179; nkx2.7vu413/vu413standard conditionsIC
              1 - 1 of 1
              Show
              Sequence Targeting Reagents
              Target Reagent Reagent Type
              isl1aMO2-isl1aMRPHLNO
              1 - 1 of 1
              Show
              Fish
              Fish
              f2Tg
              f2Tg; twu277Tg
              fb7Tg
              fb7Tg; twu277Tg
              fcu1Tg
              nkx2.5vu179/vu179
              nkx2.5vu179/vu179; f2Tg
              nkx2.5vu179/vu179; f2Tg; twu277Tg
              nkx2.5vu179/vu179; fb7Tg
              nkx2.5vu179/vu179 + MO2-isl1a
              1 - 10 of 25
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              Antibodies
              Orthology
              No data available
              Engineered Foreign Genes
              Marker Marker Type Name
              DsRed2EFGDsRed2
              EGFPEFGEGFP
              ZsYellowEFGZsYellow
              1 - 3 of 3
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              Mapping
              No data available
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              Citation
              Colombo, S., de Sena-Tomás, C., George, V., Werdich, A.A., Kapur, S., MacRae, C.A., Targoff, K.L. (2017) nkx genes establish SHF cardiomyocyte progenitors at the arterial pole and pattern the venous pole through Isl1 repression. Development (Cambridge, England). 145(3).