a zebrafish model of roberts syndrome reveals that esco2 depletion interferes with development by disrupting the cell cycle罗伯茨综合症的斑马鱼模型显示,esco2损耗干扰发展通过干扰细胞周期.pdfVIP

A Zebrafish Model of Roberts Syndrome Reveals That Esco2 Depletion Interferes with Development by Disrupting the Cell Cycle ¨ 1 ¨ 1 2 1 Maren Monnich , Zoe Kuriger , Cristin G. Print , Julia A. Horsfield * 1 Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin, New Zealand, 2 Department of Molecular Medicine and Pathology, School of Medical Sciences, and the Bioinformatics Institute, The University of Auckland, Auckland, New Zealand Abstract The human developmental diseases Cornelia de Lange Syndrome (CdLS) and Roberts Syndrome (RBS) are both caused by mutations in proteins responsible for sister chromatid cohesion. Cohesion is mediated by a multi-subunit complex called cohesin, which is loaded onto chromosomes by NIPBL. Once on chromosomes, cohesin binding is stabilized in S phase upon acetylation by ESCO2. CdLS is caused by heterozygous mutations in NIPBL or cohesin subunits SMC1A and SMC3, and RBS is caused by homozygous mutations in ESCO2. The genetic cause of both CdLS and RBS reside within the chromosome cohesion apparatus, and therefore they are collectively known as ‘‘cohesinopathies’’. However, the two syndromes have distinct phenotypes, with differences not explained by their shared ontology. In this study, we have used the zebrafish model to distinguish between developmental pathways downstream of cohesin itself, or its acetylase ESCO2. Esco2 depleted zebrafish embryos exhibit features that resemble RBS, including mitotic defects, craniofacial abnormalities and limb truncations. A microarray analysis of Esco2-depleted embryos revealed that different subsets of genes are regulated downstream of Esco2 when compared with cohesin subunit Rad21. G