title: Induction of Excess Centrosomes in Neural Progenitor Cells during the Development of Radiation-Induced Microcephaly.
abstract: 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.
authors.affiliation: Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Laboratory for Cell Asymmetry, Center for Developmental Biology, RIKEN, Kobe, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Matsuzaki
authors.affiliation: Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kato
authors.affiliation: Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kobayashi
authors.affiliation: Department of Radiation System Biology, Radiation Biology Center, Kyoto University, Kyoto, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto, Japan.
authors.forename: Kenshi
authors.initials: K
authors.lastname: Komatsu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D018385:Centrosome / Q000473:pathology* / Q000528:radiation effects*; D002540:Cerebral Cortex / Q000196:embryology / Q000528:radiation effects; D048749:Cytokinesis / Q000528:radiation effects; D005260:Female; D051379:Mice; D008831:Microcephaly / Q000473:pathology*; D058953:Neural Stem Cells / Q000473:pathology* / Q000528:radiation effects*; D011247:Pregnancy; D011833:Radiation Injuries, Experimental / Q000473:pathology*