ZFIN ID: ZDB-PUB-180802-10
Failed Progenitor Specification Underlies the Cardiopharyngeal Phenotypes in a Zebrafish Model of 22q11.2 Deletion Syndrome
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.
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
Microarrays: GEO:GSE103120
MeSH Terms:
  • 22q11 Deletion Syndrome/genetics
  • 22q11 Deletion Syndrome/pathology*
  • Animals
  • Cell Differentiation*
  • Cell Lineage
  • Embryonic Stem Cells/cytology*
  • Embryonic Stem Cells/metabolism
  • Homeobox Protein Nkx-2.5/genetics
  • Homeobox Protein Nkx-2.5/metabolism
  • Pharynx/cytology
  • Pharynx/embryology*
  • Phenotype
  • T-Box Domain Proteins/genetics
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 30067987 Full text @ Cell Rep.
FIGURES
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.
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