Neuronal apoptosis and gray matter heterotopia in microcephaly produced by cytosine arabinoside in mice
Neuronal apoptosis and gray matter heterotopia in microcephaly produced by cytosine arabinoside in mice
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DOI：
10.1016/j.brainres.2006.03.047
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发表时间：
2006-05
期刊：
影响因子：
2.9
通讯作者：
T. Takano;S. Akahori;Y. Takeuchi;M. Ohno
中科院分区：
文献类型：
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作者：
T. Takano;S. Akahori;Y. Takeuchi;M. Ohno
原发性小头畸形可伴有许多移行异常。本实验旨在探讨小鼠注射阿糖胞苷(Ara-C)后灰质异位和小头畸形的发病机制。分别于妊娠13.5天和14.5天，按30 mg/kg体重给妊娠小鼠腹腔注射阿糖胞苷，然后对其子代进行检查。胚胎15.5d，扣带回脑室带神经上皮细胞缺乏BrdU免疫反应。Nestin免疫反应阳性的放射状胶质纤维和Calretinin阳性的亚板纤维断裂。TUNEL反应在整个大脑半球都是显著的。出生后第一天，扣带回皮质下异位和侧脑室背外侧部分室管膜下结节异位开始出现。出生后32天，小头畸形明显；皮质下异位增大，但仍位于额叶和扣带回皮质。本实验证明Ara-C可诱导整个大脑半球的神经细胞凋亡。灰质异位症的免疫组织化学特征表明，皮质下异位症和室管膜下异位症均由原定位于新皮质的神经元形成。我们的结论是，伴随小头畸形的灰质异位症是由于Ara-C在未成熟发育的大脑中的毒性而引起的径向、切向和运动间神经元迁移的障碍。
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.