Variations in sister chromatid cohesion dysfunction in esco2 mutant zebrafish reflects the phenotypic diversity of Roberts Syndrome

Percival, S.M., Thomas, H.R., Amsterdam, A., Carroll, A.J., Lees, J.A., Yost, H.J., Parant, J.M.
Disease models & mechanisms   8(8): 941-55 (Journal)
Registered Authors
Amsterdam, Adam, Lees, Jaqueline, Parant, John, Percival, Stefanie M., Thomas, Holly R., Yost, H. Joseph
esco2, Sister chromatid cohesion, In vivo imaging, Zebrafish, p53, Genomic instability, Aneuploidy
MeSH Terms
  • Acetyltransferases/deficiency
  • Acetyltransferases/genetics*
  • Acetyltransferases/metabolism
  • Animals
  • Apoptosis
  • Chromatids/metabolism*
  • Chromosome Segregation
  • Chromosomes/metabolism
  • Craniofacial Abnormalities/genetics*
  • Craniofacial Abnormalities/pathology*
  • Ectromelia/genetics*
  • Ectromelia/pathology*
  • Embryo Loss/metabolism
  • Embryo Loss/pathology
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/metabolism
  • Genomic Instability
  • Hypertelorism/genetics*
  • Hypertelorism/pathology*
  • Mitotic Index
  • Models, Biological
  • Mutagenesis, Insertional/genetics
  • Mutation/genetics*
  • Neural Tube/metabolism
  • Neural Tube/pathology
  • Phenotype
  • Retroviridae/genetics
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
26044958 Full text @ Dis. Model. Mech.
Mutations in ESCO2, one of two EStablishment of COhesion factors necessary for proper Sister Chromatid Cohesion (SCC), cause a spectrum of developmental defects in the autosomal recessive disorder Roberts Syndrome (RBS), warranting in vivo analysis of the consequence of cohesion dysfunction. Through a genetic screen in zebrafish targeting embryonic lethal mutants with increased genomic instability, we have identified an esco2 mutant zebrafish. Utilizing the natural transparency of zebrafish embryos, we have developed a novel technique to observe chromosome dynamics within a single cell during mitosis in a live vertebrate embryo. Within esco2 mutant embryos, we observed premature chromatid separation, a unique chromosome scattering, prolonged mitotic delay, and genomic instability in the form of anaphase bridges and micronuclei formation. Cytogenetic studies indicated complete chromatid separation and high levels of aneuploidy within mutant embryos. Amongst aneuploid spreads, we observed predominantly decreases in chromosome number, suggesting either cells with micronuclei or micronuclei themselves are eliminated. We also demonstrated that the genomic instability leads to p53-dependent neural tube apoptosis. Surprisingly, while many cells require Esco2 to establish cohesion, 10-20% of cells have only weakened cohesion in the absence of Esco2, suggesting that compensatory cohesion mechanisms exist in these cells that undergo a normal mitotic division. These studies provide a unique in vivo vertebrate view of the mitotic defects and consequences of cohesion establishment loss, and they provide a compensation-based model to explain the RBS phenotypes.
Genes / Markers
Figure Gallery
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes