Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB/CSIC), Cantoblanco, Madrid, Spain.
Cell Death Differ. 2012 Jan;19(1):132-43. doi: 10.1038/cdd.2011.62. Epub 2011 Jun 10.
The death inducer obliterator (Dido) locus encodes three protein isoforms, of which Dido3 is the largest and most broadly expressed. Dido3 is a nuclear protein that forms part of the spindle assembly checkpoint (SAC) and is necessary for correct chromosome segregation in somatic and germ cells. Here we report that specific ablation of Dido3 function in mice causes lethal developmental defects at the onset of gastrulation. Although these defects are associated with centrosome amplification, spindle malformation and a DNA damage response, we provide evidence that embryonic lethality of the Dido3 mutation cannot be explained by its impact on chromosome segregation alone. We show that loss of Dido3 expression compromises differentiation of embryonic stem cells in vitro and of epiblast cells in vivo, resulting in early embryonic death at around day 8.5 of gestation. Close analysis of Dido3 mutant embryoid bodies indicates that ablation of Dido3, rather than producing a generalized differentiation blockade, delays the onset of lineage commitment at the primitive endoderm specification stage. The dual role of Dido3 in chromosome segregation and stem cell differentiation supports the implication of SAC components in stem cell fate decisions.
死亡诱导破坏者（Dido）基因座编码三种蛋白异构体，其中 Dido3 是最大和表达最广泛的。Dido3 是一种核蛋白，是纺锤体组装检查点（SAC）的一部分，对于体细胞和生殖细胞中正确的染色体分离是必需的。在这里，我们报告说，在小鼠中特异性消融 Dido3 功能会导致原肠胚形成时出现致命的发育缺陷。尽管这些缺陷与中心体扩增、纺锤体畸形和 DNA 损伤反应有关，但我们提供的证据表明，Dido3 突变的胚胎致死不能仅归因于其对染色体分离的影响。我们表明，Dido3 表达的缺失会损害胚胎干细胞在体外和外胚层细胞在体内的分化，导致妊娠第 8.5 天左右的早期胚胎死亡。对 Dido3 突变体胚状体的仔细分析表明，Dido3 的消融并没有产生普遍的分化阻断，而是在原始内胚层特化阶段延迟了谱系承诺的开始。Dido3 在染色体分离和干细胞分化中的双重作用支持 SAC 成分在干细胞命运决定中的作用。
