PUBLICATION

Failed Progenitor Specification Underlies the Cardiopharyngeal Phenotypes in a Zebrafish Model of 22q11.2 Deletion Syndrome

Authors
Guner-Ataman, B., González-Rosa, J.M., Shah, H.N., Butty, V.L., Jeffrey, S., Abrial, M., Boyer, L.A., Burns, C.G., Burns, C.E.
ID
ZDB-PUB-180802-10
Date
2018
Source
Cell Reports   24: 1342-1354.e5 (Journal)
Registered Authors
Burns (Erter), Caroline, Burns, Geoff, Gonzalez-Rosa, Juan Manuel
Keywords
22q11, DiGeorge, Tbx1, arch artery, cardiopharyngeal, heart, nkx2.5, progenitor, zebrafish
Datasets
GEO:GSE103120
MeSH Terms
  • Embryonic Stem Cells/cytology*
  • Embryonic Stem Cells/metabolism
  • Homeobox Protein Nkx-2.5/genetics
  • Homeobox Protein Nkx-2.5/metabolism
  • Pharynx/cytology
  • Pharynx/embryology*
  • 22q11 Deletion Syndrome/genetics
  • 22q11 Deletion Syndrome/pathology*
  • Cell Differentiation*
  • T-Box Domain Proteins/genetics
  • Phenotype
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Cell Lineage
  • Animals
(all 16)
PubMed
30067987 Full text @ Cell Rep.
Abstract
Microdeletions involving TBX1 result in variable congenital malformations known collectively as 22q11.2 deletion syndrome (22q11.2DS). Tbx1-deficient mice and zebrafish recapitulate several disease phenotypes, including pharyngeal arch artery (PAA), head muscle (HM), and cardiac outflow tract (OFT) deficiencies. In zebrafish, these structures arise from nkx2.5+ progenitors in pharyngeal arches 2-6. Because pharyngeal arch morphogenesis is compromised in Tbx1-deficient animals, the malformations were considered secondary. Here, we report that the PAA, HM, and OFT phenotypes in tbx1 mutant zebrafish are primary and arise prior to pharyngeal arch morphogenesis from failed specification of the nkx2.5+ pharyngeal lineage. Through in situ analysis and lineage tracing, we reveal that nkx2.5 and tbx1 are co-expressed in this progenitor population. Furthermore, we present evidence suggesting that gdf3-ALK4 signaling is a downstream mediator of nkx2.5+ pharyngeal lineage specification. Collectively, these studies support a cellular mechanism potentially underlying the cardiovascular and craniofacial defects observed in the 22q11.2DS population.
Genes / Markers
Figures
Figure Gallery (13 images) / 2
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cn2TgTransgenic Insertion
    fb3TgTransgenic Insertion
      fb7TgTransgenic Insertion
        fb9TgTransgenic Insertion
          fb20a
            Small Deletion
            fb23TgTransgenic Insertion
              fb25TgTransgenic Insertion
                la116TgTransgenic Insertion
                  tu285
                    Point Mutation
                    1 - 9 of 9
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                    Human Disease / Model
                    Human Disease Fish Conditions Evidence
                    velocardiofacial syndromeTAS
                    1 - 1 of 1
                    Show
                    Sequence Targeting Reagents
                    Target Reagent Reagent Type
                    gdf3CRISPR3-gdf3CRISPR
                    1 - 1 of 1
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                    Fish
                    Antibodies
                    Orthology
                    No data available
                    Engineered Foreign Genes
                    Marker Marker Type Name
                    AmCyanEFGAmCyan
                    CreEFGCre
                    GFPEFGGFP
                    KaedeEFGKaede
                    LacZEFGLacZ
                    mKate2EFGmKate2
                    ZsYellowEFGZsYellow
                    1 - 7 of 7
                    Show
                    Mapping
                    No data available