Disruption of Aspm causes microcephaly with abnormal neuronal differentiation
Disruption of Aspm causes microcephaly with abnormal neuronal differentiation
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DOI：
10.1016/j.braindev.2013.10.006
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发表时间：
2014-09-01
影响因子：
1.7
通讯作者：
Fushiki, Shinji
中科院分区：
文献类型：
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作者：
Fujimori, Akira;Itoh, Kyoko;Fushiki, Shinji
目的：在原发性小头畸形患者中检测到一些ASPM突变。为了评价ASPM在脑发育中的作用，我们建立了人常染色体隐性遗传性原发性小头畸形5（MCPH 5）模型动物。研究方法：在Aspin基因敲除小鼠中，Aspm基因的外显子2-3被一对loxP信号所包围，使得cre重组酶活性频繁地将等位基因从野生型转换为空合子，正如孟德尔遗传所预期的那样。我们使用免疫组织化学和形态测量学精确地分析了成人和胎儿的大脑。结果：Aspm（-/-）小鼠成年期脑体积较小，以大脑体积最小。在躯体感觉皮层的桶场，与Aspm（+/+）小鼠相比，Aspm（-/-）小鼠的I层显著较厚，而VI层显著较薄。与Aspin（+/+）小鼠相比，Aspm（-/-）小鼠在胚胎16.5天的细胞总数和皮质板厚度显著减少。此外，Aspin（-/-）小鼠的亚板中转录因子如Tbrl和Satb 2的表达显著增加。结论：ASp 171对神经干/祖细胞的增殖和分化具有重要作用。Aspm基因缺失模型为获得性小头畸形提供了一种新的发病机制，这种畸形可能是由子宫内暴露于已知和未知的致畸剂引起的。(C)2013年日本儿童神经病学学会。Elsevier B. V.出版，保留所有权利。
Aims: A number of ASPM mutations have been detected in primary microcephaly patients. In order to evaluate the function of ASPM in brain development, we generated model animals of human autosomal recessive primary microcephaly-5 (MCPH5). Methods: In the Aspin knock-out mice, the exon 2-3 of the Aspm gene was encompassed by a pair of loxP signals so that cre-recombinase activity switched the allele from wild-type to null zygotes as frequently, as expected from the Mendelian inheritance. We precisely analyzed the brains of adults and fetuses using immunohistochemistry and morphometry. Results: The adult brains of the Aspm(-/-) mice were smaller, especially in the cerebrum. In the barrel field of the somatosensory cortex, layer I was significantly thicker, whereas layer VI was significantly thinner in Aspm(-/-) mice, compared with Aspm(+/+) mice. The total number of cells and the thickness of the cortical plate at embryonic day 16.5 was significantly decreased in Aspm(-/-) mice, compared with Aspin(+/+) mice. Furthermore, the expression of transcription factors, such as Tbrl and Satb2, was significantly increased in the subplate of the Aspin(-/-) mice. Conclusions: The results suggested that ASp171 is essential to the proliferation and differentiation of neural stem/progenitor cells. The Aspm gene loss model provided a novel pathogenetic insight into acquired microcephaly, which can be caused by in utero exposure to both known and unknown teratogens. (C) 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.