Disruption of Aspm causes microcephaly with abnormal neuronal differentiation.
OBJECTIVE
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.
Heavy-Ion Radiobiology Research Group, Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.
Akira
A
Fujimori
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.
Kyoko
K
Itoh
Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Shoko
S
Goto
Heavy-Ion Radiobiology Research Group, Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.
Hirokazu
H
Hirakawa
Heavy-Ion Radiobiology Research Group, Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.
Bing
B
Wang
Heavy-Ion Radiobiology Research Group, Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.
Toshiaki
T
Kokubo
Heavy-Ion Radiobiology Research Group, Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.
Seiji
S
Kito
Heavy-Ion Radiobiology Research Group, Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.
Satoshi
S
Tsukamoto
Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Shinji
S
Fushiki
D000818:Animals; D001921:Brain / Q000002:abnormalities; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D013737:Testis / Q000002:abnormalities
C512460:ASPM protein, mouse; D002148:Calmodulin-Binding Proteins; D009419:Nerve Tissue Proteins
ASPM; Cortex; Differentiation; Knock-out mice; Microcephaly