Department of Pediatrics, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Dev Cell. 2010 Jun 15;18(6):913-26. doi: 10.1016/j.devcel.2010.05.017.
Centriole duplication occurs once per cell cycle, ensuring that each cell contains two centrosomes, each containing a mother-daughter pair of tightly engaged centrioles at mitotic entry. Loss of the tight engagement between mother and daughter centrioles appears to license the next round of centriole duplication. However, the molecular mechanisms regulating this process remain largely unknown. Mutations in CDK5RAP2, which encodes a centrosomal protein, cause autosomal recessive primary microcephaly in humans. Here we show that CDK5RAP2 loss of function in mice causes centriole amplification with a preponderance of single, unpaired centrioles and increased numbers of daughter-daughter centriole pairs. These results indicate that CDK5RAP2 is required to maintain centriole engagement and cohesion, thereby restricting centriole replication. Early in mitosis, amplified centrosomes assemble multipolar spindles in CDK5RAP2 mutant cells. Moreover, both mother and daughter centrioles are amplified and the excess mother centrioles template multiple primary cilia in CDK5RAP2 mutant cells.
中心体复制发生在每个细胞周期一次，确保每个细胞含有两个中心体，每个中心体在有丝分裂进入时含有一对紧密结合的母-子中心粒。母-子中心粒之间紧密结合的丧失似乎允许下一轮中心体复制。然而，调节这个过程的分子机制在很大程度上仍然未知。编码中心体蛋白的 CDK5RAP2 基因突变会导致人类常染色体隐性原发性小头畸形。在这里，我们表明 CDK5RAP2 在小鼠中的功能丧失会导致中心体扩增，表现为大量单一、未配对的中心粒和更多的子-子中心粒对。这些结果表明 CDK5RAP2 是维持中心体结合和凝聚所必需的，从而限制中心体复制。在有丝分裂早期，扩增的中心体在 CDK5RAP2 突变细胞中组装多极纺锤体。此外，母-子中心粒都被扩增，多余的母中心粒模板在 CDK5RAP2 突变细胞中形成多个初级纤毛。
