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Induction of Excess Centrosomes in Neural Progenitor Cells during the Development of Radiation-Induced Microcephaly.

Shimada M, Matsuzaki F, Kato A, Kobayashi J, Matsumoto T, Komatsu K - PLoS ONE (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Disruption of the apical layer in the mouse embryonic cerebral cortex after IR exposure.Mouse embryos at E13.5 were irradiated with 1 or 2 Gy and the brains were sampled 24 h later and stained with antibodies against (A) ZO1 (green) and Sox2 (blue), used as markers of adherence junctions and neural progenitors, respectively; and (B) γ-tubulin (green), used as a spindle marker. VZ: ventricular zone; SVZ: subventricular zone. Scale bar: 100 μm.
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pone.0158236.g003: Disruption of the apical layer in the mouse embryonic cerebral cortex after IR exposure.Mouse embryos at E13.5 were irradiated with 1 or 2 Gy and the brains were sampled 24 h later and stained with antibodies against (A) ZO1 (green) and Sox2 (blue), used as markers of adherence junctions and neural progenitors, respectively; and (B) γ-tubulin (green), used as a spindle marker. VZ: ventricular zone; SVZ: subventricular zone. Scale bar: 100 μm.

Mentions: Cell positioning at the apical layer is considered to play an indispensable role in the proliferation of neural progenitors [22]. Therefore, we investigated the apical structure by immunostaining with antibodies against ZO-1 and γ-tubulin, markers of adherence junctions and spindles, respectively. The ZO-1- and γ-tubulin-positive cells showed a flat bottom of the apical layer in control embryos, but this was disrupted at 4 and 24 h after 1 Gy γ-ray exposure and subsequently restored, with the peak disruption occurring at 12 h (Fig 3A). However, numerous γ-tubulin-positive cells were still detected in the basal layer, which agreed with the immunostaining observed using the Tuj1 antibody (Fig 2A). Moreover, the apical structure in the cerebral cortex was more severely disrupted in embryos irradiated with 2 Gy than in the 1 Gy irradiated embryos (Fig 3B).


Induction of Excess Centrosomes in Neural Progenitor Cells during the Development of Radiation-Induced Microcephaly.

Shimada M, Matsuzaki F, Kato A, Kobayashi J, Matsumoto T, Komatsu K - PLoS ONE (2016)

Disruption of the apical layer in the mouse embryonic cerebral cortex after IR exposure.Mouse embryos at E13.5 were irradiated with 1 or 2 Gy and the brains were sampled 24 h later and stained with antibodies against (A) ZO1 (green) and Sox2 (blue), used as markers of adherence junctions and neural progenitors, respectively; and (B) γ-tubulin (green), used as a spindle marker. VZ: ventricular zone; SVZ: subventricular zone. Scale bar: 100 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4930206&req=5

pone.0158236.g003: Disruption of the apical layer in the mouse embryonic cerebral cortex after IR exposure.Mouse embryos at E13.5 were irradiated with 1 or 2 Gy and the brains were sampled 24 h later and stained with antibodies against (A) ZO1 (green) and Sox2 (blue), used as markers of adherence junctions and neural progenitors, respectively; and (B) γ-tubulin (green), used as a spindle marker. VZ: ventricular zone; SVZ: subventricular zone. Scale bar: 100 μm.
Mentions: Cell positioning at the apical layer is considered to play an indispensable role in the proliferation of neural progenitors [22]. Therefore, we investigated the apical structure by immunostaining with antibodies against ZO-1 and γ-tubulin, markers of adherence junctions and spindles, respectively. The ZO-1- and γ-tubulin-positive cells showed a flat bottom of the apical layer in control embryos, but this was disrupted at 4 and 24 h after 1 Gy γ-ray exposure and subsequently restored, with the peak disruption occurring at 12 h (Fig 3A). However, numerous γ-tubulin-positive cells were still detected in the basal layer, which agreed with the immunostaining observed using the Tuj1 antibody (Fig 2A). Moreover, the apical structure in the cerebral cortex was more severely disrupted in embryos irradiated with 2 Gy than in the 1 Gy irradiated embryos (Fig 3B).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto, Japan.

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.

No MeSH data available.


Related in: MedlinePlus