title: Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome.
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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Percival
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Holly R
authors.initials: HR
authors.lastname: Thomas
authors.affiliation: David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Amsterdam
authors.affiliation: Department of Clinical and Diagnostic Science, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.affiliation: David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Lees
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: H Joseph
authors.initials: HJ
authors.lastname: Yost
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA jparant@uab.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Parant
mesh_terms: D000123:Acetyltransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002842:Chromatids / Q000378:metabolism*; D020090:Chromosome Segregation; D002875:Chromosomes / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000473:pathology*; D004480:Ectromelia / Q000235:genetics* / Q000473:pathology*; D020964:Embryo Loss / Q000378:metabolism / Q000473:pathology; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D042822:Genomic Instability; D006972:Hypertelorism / Q000235:genetics* / Q000473:pathology*; D008940:Mitotic Index; D008954:Models, Biological; D016254:Mutagenesis, Insertional / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D054259:Neural Tube / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012190:Retroviridae / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: C561285:Esco2 protein, zebrafish; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; D000123:Acetyltransferases
keywords: Aneuploidy; Genomic instability; In vivo imaging; Sister chromatid cohesion; Zebrafish; esco2; p53