Neuronal apoptosis and gray matter heterotopia in microcephaly produced by cytosine arabinoside in mice.
Primary microcephaly can be accompanied by numerous migration anomalies. This experiment was undertaken to examine the pathogenesis of gray matter heterotopia and microcephaly that is produced after administering cytosine arabinoside (Ara-C) to mice. Pregnant mice were intraperitoneally injected with Ara-C at 30 mg/kg body weight on days 13.5 and 14.5 of gestation, and then their offspring were examined. On embryonic day 15.5, in the ventricular zone of the cingulate cortex, the neuroepithelial cells lacked BrdU immunoreactivity. Nestin-immunoreactive radial glial fibers and calretinin-positive subplate fibers were disrupted. TUNEL reaction was remarkable throughout the cerebral hemisphere. Subcortical heterotopia in the cingulate cortex and subependymal nodular heterotopia in the dorsolateral part of the lateral ventricles became detectable by the first day after birth. Thirty-two days after birth, microcephaly was apparent; subcortical heterotopia was observed to have increased in size while it was still located in the frontal and cingulate cortices. This experiment demonstrated that Ara-C induces neuronal apoptosis throughout the cerebral hemisphere. The immunohistochemical characteristics in the gray matter heterotopia suggest that both the subcortical and the subependymal heterotopias were formed by neurons originally committed to the neocortex. We conclude that the gray matter heterotopia that accompanies the microcephaly was produced by a disturbance of radial, tangential, and interkinetic neuronal migrations due to the toxicity of Ara-C in the immature developing brain.
Takano
Tomoyuki
T
Department of Pediatrics, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan. tmyktkn@belle.shiga-med.ac.jp
Akahori
Shie
S
Takeuchi
Yoshihiro
Y
Ohno
Masaki
M
D000818:Animals; D000831:Animals, Newborn; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D001973:Bromodeoxyuridine; D064032:Calbindin 2; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000187:drug effects* / Q000503:physiopathology; D002828:Choristoma / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D003561:Cytarabine / Q000009:adverse effects*; D004195:Disease Models, Animal; D051379:Mice; D008813:Mice, Inbred ICR; D008831:Microcephaly / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology; D009421:Nervous System Malformations / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; C576511:Calb2 protein, mouse; D064032:Calbindin 2; D008869:Microtubule-Associated Proteins; D064030:S100 Calcium Binding Protein G; D003561:Cytarabine; D001973:Bromodeoxyuridine