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Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome.
- Source :
-
Disease models & mechanisms [Dis Model Mech] 2015 Aug 01; Vol. 8 (8), pp. 941-55. Date of Electronic Publication: 2015 Jun 04. - Publication Year :
- 2015
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Abstract
- 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 that have 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 predominantly observed decreases in chromosome number, suggesting that either cells with micronuclei or micronuclei themselves are eliminated. We also demonstrated that the genomic instability leads to p53-dependent neural tube apoptosis. Surprisingly, although many cells required Esco2 to establish cohesion, 10-20% of cells had 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.<br /> (© 2015. Published by The Company of Biologists Ltd.)
- Subjects :
- Acetyltransferases deficiency
Acetyltransferases metabolism
Animals
Apoptosis
Chromosome Segregation
Chromosomes metabolism
Embryo Loss metabolism
Embryo Loss pathology
Embryo, Nonmammalian cytology
Embryo, Nonmammalian metabolism
Genomic Instability
Mitotic Index
Models, Biological
Mutagenesis, Insertional genetics
Neural Tube metabolism
Neural Tube pathology
Phenotype
Retroviridae genetics
Tumor Suppressor Protein p53 metabolism
Zebrafish embryology
Zebrafish Proteins deficiency
Zebrafish Proteins metabolism
Acetyltransferases genetics
Chromatids metabolism
Craniofacial Abnormalities genetics
Craniofacial Abnormalities pathology
Ectromelia genetics
Ectromelia pathology
Hypertelorism genetics
Hypertelorism pathology
Mutation genetics
Zebrafish genetics
Zebrafish Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1754-8411
- Volume :
- 8
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Disease models & mechanisms
- Publication Type :
- Academic Journal
- Accession number :
- 26044958
- Full Text :
- https://doi.org/10.1242/dmm.019059