Akira Fujimori1, Kyoko Itoh2, Shoko Goto3, Hirokazu Hirakawa1, Bing Wang1, Toshiaki Kokubo1, Seiji Kito1, Satoshi Tsukamoto1, Shinji Fushiki3. 1. Heavy-Ion Radiobiology Research Group, Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan. 2. Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address: kxi14@koto.kpu-m.ac.jp. 3. Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Abstract
AIMS: A number of ASPM mutations have been detected in primary microcephaly patients. In order to evaluate the function of ASPM in brain development, we generated model animals of human autosomal recessive primary microcephaly-5 (MCPH5). METHODS: In the Aspm knock-out mice, the exon 2-3 of the Aspm gene was encompassed by a pair of loxP signals so that cre-recombinase activity switched the allele from wild-type to null zygotes as frequently, as expected from the Mendelian inheritance. We precisely analyzed the brains of adults and fetuses using immunohistochemistry and morphometry. RESULTS: The adult brains of the Aspm(-/-) mice were smaller, especially in the cerebrum. In the barrel field of the somatosensory cortex, layer I was significantly thicker, whereas layer VI was significantly thinner in Aspm(-/-) mice, compared with Aspm(+/+) mice. The total number of cells and the thickness of the cortical plate at embryonic day 16.5 was significantly decreased in Aspm(-/-) mice, compared with Aspm(+/+) mice. Furthermore, the expression of transcription factors, such as Tbr1 and Satb2, was significantly increased in the subplate of the Aspm(-/-) mice. CONCLUSIONS: The results suggested that Aspm is essential to the proliferation and differentiation of neural stem/progenitor cells. The Aspm gene loss model provided a novel pathogenetic insight into acquired microcephaly, which can be caused by in utero exposure to both known and unknown teratogens.
AIMS: A number of ASPM mutations have been detected in primary microcephalypatients. In order to evaluate the function of ASPM in brain development, we generated model animals of human autosomal recessive primary microcephaly-5 (MCPH5). METHODS: In the Aspm knock-out mice, the exon 2-3 of the Aspm gene was encompassed by a pair of loxP signals so that cre-recombinase activity switched the allele from wild-type to null zygotes as frequently, as expected from the Mendelian inheritance. We precisely analyzed the brains of adults and fetuses using immunohistochemistry and morphometry. RESULTS: The adult brains of the Aspm(-/-) mice were smaller, especially in the cerebrum. In the barrel field of the somatosensory cortex, layer I was significantly thicker, whereas layer VI was significantly thinner in Aspm(-/-) mice, compared with Aspm(+/+) mice. The total number of cells and the thickness of the cortical plate at embryonic day 16.5 was significantly decreased in Aspm(-/-) mice, compared with Aspm(+/+) mice. Furthermore, the expression of transcription factors, such as Tbr1 and Satb2, was significantly increased in the subplate of the Aspm(-/-) mice. CONCLUSIONS: The results suggested that Aspm is essential to the proliferation and differentiation of neural stem/progenitor cells. The Aspm gene loss model provided a novel pathogenetic insight into acquired microcephaly, which can be caused by in utero exposure to both known and unknown teratogens.
Authors: Débora Cabral de Carvalho Corrêa; Indhira Dias Oliveira; Bruna Mascaro Cordeiro; Frederico Adolfo Silva; Maria Teresa de Seixas Alves; Nasjla Saba-Silva; Andrea Maria Capellano; Patrícia Dastoli; Sergio Cavalheiro; Silvia Regina Caminada de Toledo Journal: Childs Nerv Syst Date: 2020-06-26 Impact factor: 1.532
Authors: Patricia P Garcez; Javier Diaz-Alonso; Ivan Crespo-Enriquez; Diogo Castro; Donald Bell; François Guillemot Journal: Nat Commun Date: 2015-03-10 Impact factor: 14.919