ASPM is a major determinant of cerebral cortical size
ASPM is a major determinant of cerebral cortical size
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DOI：
10.1038/ng995
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发表时间：
2002-10-01
期刊：
影响因子：
30.8
通讯作者：
Woods, CG
中科院分区：
文献类型：
--
作者：
Bond, J;Roberts, E;Woods, CG
哺乳动物进化中最显著的趋势之一是大脑皮层的体积大幅增加，特别是在灵长类动物中。常染色体隐性遗传性原发性小头畸形(MCPH)患者的大脑皮质较小，但在其他方面大体正常，并伴有轻度至中度智力低下(1-4)。与这种情况相关的基因为大脑皮层的发育和进化提供了潜在的见解。在这里，我们表明MCPH最常见的原因是ASPM的纯合突变，这是人类的果蝇异常纺锤体基因(Asp)的同源基因(5)，对于胚胎神经母细胞的正常有丝分裂纺锤体功能是必不可少的(6)。小鼠基因Aspm在胎儿期大脑皮层神经发生的主要部位特异表达。值得注意的是，预测的ASPM蛋白在苍蝇、小鼠和人类之间系统性地编码大量重复的‘IQ’结构域，Aspm和ASPM之间的主要区别是IQ结构域的单个大插入编码。我们的结果和进化的考虑表明，大脑的大小在一定程度上是通过调节神经前体细胞中有丝分裂的纺锤体活动来控制的。
One of the most notable trends in mammalian evolution is the massive increase in size of the cerebral cortex, especially in primates. Humans with autosomal recessive primary microcephaly (MCPH) show a small but otherwise grossly normal cerebral cortex associated with mild to moderate mental retardation(1-4). Genes linked to this condition offer potential insights into the development and evolution of the cerebral cortex. Here we show that the most common cause of MCPH is homozygous mutation of ASPM, the human ortholog of the Drosophila melanogaster abnormal spindle gene (asp)(5), which is essential for normal mitotic spindle function in embryonic neuroblasts(6). The mouse gene Aspm is expressed specifically in the primary sites of prenatal cerebral cortical neurogenesis. Notably, the predicted ASPM proteins encode systematically larger numbers of repeated 'IQ' domains between flies, mice and humans, with the predominant difference between Aspm and ASPM being a single large insertion coding for IQ domains. Our results and evolutionary considerations suggest that brain size is controlled in part through modulation of mitotic spindle activity in neuronal progenitor cells.