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

神经元迁移障碍在阿糖胞苷诱导小鼠小头畸形中的作用

• 批准号: 17591082
• 负责人: TAKANO Tomoyuki
• 金额: $ 2.18万
• 依托单位: Shiga University of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591082/
• 关键词: microcephaly; gray matter heterotopia; cortical dysplasia; neuronal migration; apoptosis; mice; 異所性石灰質

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.

原发性小头畸形是多种遗传和染色体缺陷以及环境损伤的结果。小头畸形可伴有许多迁移异常，包括灰质异位。核苷类似物阿糖胞苷（Ara-C）可抑制增殖细胞的DNA合成。在妊娠期间给小鼠施用阿糖胞苷会导致其后代出现具有遗传异常的细胞结构和灰质异位症的小头畸形。进行该实验以检查异常神经元迁移在通过给予小鼠Ara-C产生的小头畸形发展中的作用。在妊娠第13.5天和第14.5天，向妊娠小鼠腹腔内注射30 mg/kg体重的Ara-C。为了研究细胞增殖，5-溴脱氧尿苷（BrdU），S期标记物，在妊娠第15.5天腹腔内注射（50 μg/g体重）。在胚胎第15.5天，在扣带皮层的脑室区，神经上皮细胞缺乏BrdU免疫反应。巢蛋白免疫反应阳性的放射状胶质纤维和calretinin阳性的亚板纤维被破坏。末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记（TUNEL）反应是显着的整个大脑半球。扣带回皮质和室管膜下结节性异位在侧脑室背外侧部分的皮质下异位分别在出生后第1天和第13天检测到。出生后32天，小头畸形明显;皮质下异位的大小增加，仍然位于额叶和扣带回皮质。本实验表明，Ara-C诱导整个大脑半球的神经元凋亡。这表明，灰质异位症，伴随着小头畸形是由径向和切向神经元迁移的干扰，由于阿糖胞苷在未成熟的发育中的大脑的毒性。

项目成果

脳皮質形成異常および腹腔内石灰化をともなったPeters' anomalyの1例

Peters畸形伴大脑皮质发育不良并腹膜内钙化1例

• 发表时间: 2005
• 期刊: 小児科臨床 68(3)
• 作者: Matsuzaki S;Shinozaki Kobayashi N;Agematsu K.;岩見美香
• 通讯作者: 岩見美香

Neuronal apoptosis and gray matter heterotopia in microcephaly produced by cytosine arabinoside in mice

• DOI: 10.1016/j.brainres.2006.03.047
• 发表时间: 2006-05
• 期刊: Brain Research
• 影响因子: 2.9
• 作者: T. Takano;S. Akahori;Y. Takeuchi;M. Ohno

Experimental cortical dysplasia following ibotenate administration in hamsters : pathogenesis of microgyria and associated gray matter heterotopia.

仓鼠给予鹅膏酯后实验性皮质发育不良：小脑回和相关灰质异位的发病机制。

• 发表时间: 2005
• 期刊: Congenital Anomalies 45
• 作者: Yoshikawa K;Matsui E;Kaneko H;Fukao T;Inoue R;Teramoto T;Shinoda S;Fukutomi 0;Aoki M;Kasahara K;Kondo N;Tomoyuki Takano
• 通讯作者: Tomoyuki Takano

一過性脳梁膨大部病変を認めたインフルエンザ脳症の2例

胼胝体壶腹部短暂性病变流感脑病二例

• 发表时间: 2005
• 期刊: 小児科 46(12)
• 作者: Yasui K;Kobayashi N;Yamazaki T;Agematsu K;Matsuzaki S;Ito S;Nakata S;Baba A;Koike K.;伊藤英介
• 通讯作者: 伊藤英介

Frontal-dominant white matter lesions following congenital rubella and cytomegalovirus infection

先天性风疹和巨细胞病毒感染后额叶主导的白质病变

• 发表时间: 2006
• 期刊: Journal of Perinatal Medicine 34
• 作者: Sekiguchi Y;Yasui K;Yamazaki T;Agematsu K;Kobayashi N;Koike K;Tomoyuki Takano
• 通讯作者: Tomoyuki Takano