Induction of Excess Centrosomes in Neural Progenitor Cells during the Development of Radiation-Induced Microcephaly.
Induction of Excess Centrosomes in Neural Progenitor Cells during the Development of Radiation-Induced Microcephaly.
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辐射诱导的小头畸形的发育过程中，神经祖细胞中过量的中心体诱导。
DOI：
10.1371/journal.pone.0158236
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Komatsu K
中科院分区：
文献类型：
--
作者：
Shimada M;Matsuzaki F;Kato A;Kobayashi J;Matsumoto T;Komatsu K
胚胎脑是最易受电离辐射伤害的组织之一。在这项研究中，我们发现，电离辐射诱导小鼠大脑皮层的神经祖细胞的凋亡，并存活的祖细胞随后发展出相当数量的额外中心体。当第13.5天的小鼠胚胎暴露于γ射线时，大脑尺寸以剂量依赖性方式显著减小，并且这些尺寸减小持续到出生。caspase-3抗体的免疫染色显示，分别暴露于1和2戈伊后4小时，35%和40%的神经前体细胞发生凋亡，这是伴随着在未照射的小鼠中有丝分裂纺锤体定位的顶端层的破坏。在24小时后，1戈伊照射，凋亡细胞被完全消除，增殖恢复到一个类似于未照射的细胞的水平，但许多纺锤体定位于外的顶端层。同样，异常的胞质分裂，其中包括多极分裂和中心体聚集，观察到19%和24%的存活神经前体细胞在48小时后照射1和2戈伊，分别。由于这些来自过量中心体的胞质分裂畸变导致生长延迟和有丝分裂灾难介导的细胞消除，我们的研究结果表明，除了在辐射暴露的早期阶段的细胞凋亡外，辐射诱导的中心体过度复制可能导致神经祖细胞的耗竭，从而导致小头畸形。
The embryonic brain is one of the tissues most vulnerable to ionizing radiation. In this study, we showed that ionizing radiation induces apoptosis in the neural progenitors of the mouse cerebral cortex, and that the surviving progenitor cells subsequently develop a considerable amount of supernumerary centrosomes. When mouse embryos at Day 13.5 were exposed to γ-rays, brains sizes were reduced markedly in a dose-dependent manner, and these size reductions persisted until birth. Immunostaining with caspase-3 antibodies showed that apoptosis occurred in 35% and 40% of neural progenitor cells at 4 h after exposure to 1 and 2 Gy, respectively, and this was accompanied by a disruption of the apical layer in which mitotic spindles were positioned in unirradiated mice. At 24 h after 1 Gy irradiation, the apoptotic cells were completely eliminated and proliferation was restored to a level similar to that of unirradiated cells, but numerous spindles were localized outside the apical layer. Similarly, abnormal cytokinesis, which included multipolar division and centrosome clustering, was observed in 19% and 24% of the surviving neural progenitor cells at 48 h after irradiation with 1 and 2 Gy, respectively. Because these cytokinesis aberrations derived from excess centrosomes result in growth delay and mitotic catastrophe-mediated cell elimination, our findings suggest that, in addition to apoptosis at an early stage of radiation exposure, radiation-induced centrosome overduplication could contribute to the depletion of neural progenitors and thereby lead to microcephaly.