新規放射線応答遺伝子ASPMの生物学的研究

We previously found that ionizing radiation (IR) commonly suppresses expression of ASPM gene, which are found mutated in a majority of human patients of familiar microcephaly (MCPH5). In pregnant mice, sub-lethal doses of IR drastically reduced the protein level of Aspm in their developing embryos, particularly in the neural stem cells that express nestins. To further investigating a cause of microcephaly, we developed a knock-out system where disruption of the Aspm gene can be controlled through Cre-loxP recombination systems. Aspm null homozygotes are obtained by mating Aspm +/- parental mice following Mendellian rule. They grew apparently healthy but had significantly small brains (85% in weight) and testes (20% in weight) compared to +/+ and +/- animals. HE staining has detected no pathological abnormality in the affected brains but loss of spermatogenesis in most seminiferous tubule. Next we destroyed the floxed Aspm genes selectively in CNS by introducing Cre expression under the murine Nestin gene promotors. A similar defect in the brain size was obtained in the homozygote animals of the floxed alleles only when Nes-Cre transgenes were inherited, while no testes were affected. Our results suggested that any synthetic suppression of Aspm can cause microcephaly phenotypes only if nestin expressing tissues are targeted during the CNS development.第34回日本分子生物学会年