Red blood cells are produced by terminal erythroid differentiation, which involves the dramatic morphological transformation of erythroblasts into enucleated reticulocytes. Microtubules are important for enucleation, but it is not known if the centrosome, a key microtubule-organizing center, is required as well. Mice lacking the conserved centrosome component, CDK5RAP2, are likely to have defective erythroid differentiation because they develop macrocytic anemia. Here, we show that fetal liver-derived, CDK5RAP2-deficient erythroid progenitors generate fewer and larger reticulocytes, hence recapitulating features of macrocytic anemia. In erythroblasts, but not in embryonic fibroblasts, loss of CDK5RAP2 or pharmacological depletion of centrosomes leads to highly aberrant spindle morphologies. Consistent with such cells exiting mitosis without chromosome segregation, tetraploidy is frequent in late-stage erythroblasts, thereby giving rise to fewer but larger reticulocytes than normal. Our results define a critical role for CDK5RAP2 and centrosomes in spindle formation specifically during blood production. We propose that disruption of centrosome and spindle function could contribute to the emergence of macrocytic anemias, for instance, due to nutritional deficiency or exposure to chemotherapy.

中文翻译：

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中心体功能在红细胞终末分化过程中至关重要


红细胞是由终末红细胞分化产生的，这涉及有红细胞向去核网织红细胞的戏剧性形态转变。微管对于去核很重要，但尚不清楚是否也需要中心体（关键的微管组织中心）。缺乏保守中心体成分 CDK5RAP2 的小鼠可能会​​出现红细胞分化缺陷，因为它们会出现大细胞性贫血。在这里，我们发现胎儿肝脏来源的、CDK5RAP2缺陷的红系祖细胞产生更少和更大的网织红细胞，因此概括了大细胞性贫血的特征。在成红细胞中，但在胚胎成纤维细胞中，CDK5RAP2 的丢失或中心体的药理耗竭会导致纺锤体形态高度异常。与此类细胞在没有染色体分离的情况下退出有丝分裂一致，四倍体在晚期成红细胞中很常见，从而产生比正常情况更少但更大的网织红细胞。我们的结果明确了 CDK5RAP2 和中心体在纺锤体形成中的关键作用，特别是在血液生产过程中。我们认为，中心体和纺锤体功能的破坏可能导致大细胞性贫血的出现，例如，由于营养缺乏或接受化疗。