The role of neuronal migration disorder in microcephaly induced by Ara-C in mice

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Primary microcephaly is the result of a variety of genetic and chromosomal defects, as well as environmental insults. Microcephaly can be accompanied by numerous migration anomalies including gray matter heterotopia. The nucleoside analog, cytosine arabinoside (Ara-C), can inhibit DNA synthesis in proliferating cells. The administration of Ara-C to mice during pregnancy gives rise to microcephaly with dysgenetic cytoarchitecture and gray matter heterotopia in their offspring. This experiment was undertaken to examine the role of abnormal neuronal migration in the development of microcephaly that is produced by giving Ara-C to mice. Pregnant mice were injected intraperitoneally with Ara-C at 30 mg/kg body weight on days 13.5 and 14.5 of gestation. For the study of cell proliferation, 5-bromodeoxyuridine (BrdU), an S-phase marker, was injected intraperitoneally on day 15.5 of gestation (50 μg/g body weight). 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. The terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (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 and the thirteenth day after birth, respectively. Thirty-two days after birth, microcephaly was apparent ; subcortical heterotopia was increased in size and still located in the frontal and cingulate cortices. This experiment demonstrated that Ara-C induces neuronal apoptosis throughout the cerebral hemisphere. This suggests that the gray matter heterotopia that accompanies the microcephaly was produced by a disturbance of radial and tangential neuronal migrations due to the toxicity of Ara-C in the immature developing brain.