Methylnitrosourea induces neural progenitor cell apoptosis and microcephaly in mouse embryos.
BACKGROUND
Prenatal exposure to methylnitrosourea (MNU), an alkylating agent, induces microcephaly in mice. However, its pathogenetic mechanism has not been clarified, especially that in the development of the cerebral cortex.


METHODS
ICR mice were treated with MNU at 10 mg/kg intraperitoneally on day 13.5 or 15.5 of gestation, and the embryos were observed histologically 24 hr after treatment with MNU or at term. To clarify the pathogenesis of microcephaly and histological changes, especially apoptosis, neurogenesis, and neural migration/positioning, we performed histological analysis employing a cell-specific labeling experiment using thymidine-like substances (BrdU, CldU, and IdU) and markers of neurons/neural stem cells.


RESULTS
Histological abnormalities of the dorsal telencephalon, and the excessive cell death of proliferative neural progenitor/stem cells were noted in the MNU-treated embryos. The highest frequencies of cell death occurred at 36 hr after MNU treatment, and little or no neurogenesis was observed in the ventricular zone of the dorsal telencephalon. Abnormality of the radial migration was caused by the reduction of radial fibers in the radial glias. Birth-date analysis revealed the abnormal positioning of neurons and aberrant lamination of the cerebral cortex.


CONCLUSIONS
Our data suggest that prenatal exposure to MNU induces the excessive cell death of neural precursor/stem cells, and the defective development of the cerebral cortex, resulting in microcephalic abnormalities.
Komada
Munekazu
M
Congenital Anomaly Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan. komada@cac.med.kyoto-u.ac.jp
Fujiyama
Fusako
F
Yamada
Shigehito
S
Shiota
Kohei
K
Nagao
Tetsuji
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004622:Embryo, Mammalian / Q000002:abnormalities* / Q000187:drug effects / Q000473:pathology; D005260:Female; D008297:Male; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D008831:Microcephaly / Q000139:chemically induced* / Q000196:embryology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology*; D013687:Telencephalon / Q000187:drug effects / Q000196:embryology / Q000473:pathology
D008770:Methylnitrosourea