PUBLICATION

Pbx4 limits heart size and fosters arch artery formation through partitioning second heart field progenitors and restricting proliferation

Authors
Holowiecki, A., Linstrum, K., Ravisankar, P., Chetal, K., Salomonis, N., Waxman, J.S.
ID
ZDB-PUB-200226-3
Date
2020
Source
Development (Cambridge, England)   147(5): (Journal)
Registered Authors
Waxman, Joshua
Keywords
Heart development, Outflow tract, Pbx transcription factor, Pharyngeal arch arteries, Second heart field, Zebrafish
Datasets
GEO:GSE126647
MeSH Terms
  • Animals
  • Aorta, Thoracic/embryology*
  • Branchial Region/cytology
  • Branchial Region/embryology*
  • Cardiomegaly/genetics*
  • Cell Proliferation/physiology
  • DNA-Binding Proteins/genetics*
  • Heart/embryology
  • Heart/physiology
  • Myocytes, Cardiac/cytology
  • Stem Cells/cytology
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics*
(all 14)
PubMed
32094112 Full text @ Development
Abstract
Vertebrate heart development requires the integration of temporally-distinct differentiating progenitors. However, few signals are understood that restrict the size of the later-differentiating outflow tract (OFT). We show that improper specification and proliferation of second heart field (SHF) progenitors in zebrafish lazarus (lzr) mutants, which lack the transcription factor Pbx4, produces enlarged hearts due to an increase in ventricular and smooth muscle cells. Specifically, Pbx4 initially promotes the partitioning of the SHF into anterior progenitors, which contribute to the OFT, and adjacent endothelial cell progenitors, which contribute to posterior pharyngeal arches. Subsequently, Pbx4 limits SHF progenitor (SHFP) proliferation. Single-cell RNA sequencing of nkx2.5+ cells revealed previously unappreciated distinct differentiation states and progenitor subpopulations that normally reside within the SHF and arterial pole of the heart. Specifically, Pbx4-deficient nkx2.5+ SHFPs have less distinct transcriptional profiles and display characteristics of normally discrete proliferative progenitor and anterior, differentiated cardiomyocyte populations. Therefore, our data indicate that the generation of proper OFT size and arch arteries requires Pbx-dependent stratification of unique differentiation states to facilitate both homeotic-like transformations and limit progenitor production within the SHF.
Genes / Markers
Marker Marker Type Name
bmp4GENEbone morphogenetic protein 4
cdkn1aGENEcyclin dependent kinase inhibitor 1A
cdkn2cGENEcyclin-dependent kinase inhibitor 2C (p18, inhibits CDK4)
crip2GENEcysteine-rich protein 2
foxa2GENEforkhead box A2
gata4GENEGATA binding protein 4
hand2GENEheart and neural crest derivatives expressed 2
kdrlGENEkinase insert domain receptor like
lft2GENElefty2
ltbp3GENElatent transforming growth factor beta binding protein 3
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Figures
Figure Gallery (8 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
fb7Tg + MO2-pbx4 + MO3-pbx4standard conditionsPrim-5
fb7Tg + MO2-pbx4 + MO3-pbx4standard conditionsPrim-5
pbx4b557/b557standard conditionsPrim-5
pbx4b557/b557standard conditionsPrim-5
pbx4b557/b557standard conditionsPrim-5
pbx4b557/b557standard conditionsPrim-15
pbx4b557/b557standard conditionsPrim-25
pbx4b557/b557standard conditionsPrim-25
pbx4b557/b557standard conditionsPrim-25
pbx4b557/b557standard conditionsLong-pec
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b557
    		Point Mutation
    ci5TgTransgenic Insertion
      cz1701TgTransgenic Insertion
        f2TgTransgenic Insertion
          fb7TgTransgenic Insertion
            fb9TgTransgenic Insertion
              hsc6TgTransgenic Insertion
                sd22TgTransgenic Insertion
                  ubs1TgTransgenic Insertion
                    1 - 9 of 9
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                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    Target Reagent Reagent Type
                    pbx4MO2-pbx4MRPHLNO
                    pbx4MO3-pbx4MRPHLNO
                    tp53MO4-tp53MRPHLNO
                    1 - 3 of 3
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                    Fish
                    Antibodies
                    Orthology
                    Engineered Foreign Genes
                    Marker Marker Type Name
                    DsRed2EFGDsRed2
                    EGFPEFGEGFP
                    KaedeEFGKaede
                    KikGREFGKikGR
                    mCherryEFGmCherry
                    ZsYellowEFGZsYellow
                    1 - 6 of 6
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                    Mapping
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                    Citation
                    Holowiecki, A., Linstrum, K., Ravisankar, P., Chetal, K., Salomonis, N., Waxman, J.S. (2020) Pbx4 limits heart size and fosters arch artery formation through partitioning second heart field progenitors and restricting proliferation. Development (Cambridge, England). 147(5):.