Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome.
Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome.
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DOI：
10.1242/dmm.019059
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发表时间：
2015-08-01
影响因子：
4.3
通讯作者：
Parant JM
中科院分区：
文献类型：
--
作者：
Percival SM;Thomas HR;Amsterdam A;Carroll AJ;Lees JA;Yost HJ;Parant JM
ESCO 2突变是姐妹染色单体凝聚力（SCC）所必需的两个凝聚力因子之一，在常染色体隐性遗传疾病罗伯茨综合征（RBS）中引起一系列发育缺陷，从而阻碍了对凝聚力功能障碍后果的体内分析。通过对斑马鱼进行基因筛选，发现胚胎致死突变体增加了基因组的不稳定性，我们确定了一种esco 2突变斑马鱼。利用斑马鱼胚胎的天然透明性，我们开发了一种新的技术来观察活脊椎动物胚胎有丝分裂过程中单个细胞内的染色体动态。在Esco 2突变胚胎中，我们观察到过早的染色单体分离，独特的染色体分散，延长有丝分裂延迟，后期桥和微核形成形式的基因组不稳定性。细胞遗传学研究表明，完全染色单体分离和高水平的非整倍体突变胚胎。在非整倍体扩散中，我们主要观察到染色体数目减少，这表明具有微核的细胞或微核本身被消除。我们还证明了基因组的不稳定性导致p53依赖的神经管凋亡。令人惊讶的是，尽管许多细胞需要Esco 2来建立凝聚力，但在Esco 2不存在的情况下，10-20%的细胞仅具有减弱的凝聚力，这表明在这些经历正常有丝分裂的细胞中存在补偿凝聚力机制。这些研究提供了一个独特的有丝分裂缺陷和凝聚力建立损失的后果在体内脊椎动物的观点，他们提供了一个补偿为基础的模型来解释RBS表型。摘要：斑马鱼esco 2突变体的体内分析揭示了广泛的基因组不稳定性和DNA损伤反应途径的激活，尽管一些细胞具有补偿性凝聚力并正常分裂。
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. Summary: In vivo analysis of zebrafish esco2 mutants reveals extensive genomic instability and activation of DNA-damage-response pathways, although some cells have compensatory cohesion and divide normally.