Gilmore Edward C, Walsh Christopher A
Division of Pediatric Neurology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
Wiley Interdiscip Rev Dev Biol. 2013 Jul;2(4):461-78. doi: 10.1002/wdev.89. Epub 2012 Oct 4.
The study of human developmental microcephaly is providing important insights into brain development. It has become clear that developmental microcephalies are associated with abnormalities in cellular production, and that the pathophysiology of microcephaly provides remarkable insights into how the brain generates the proper number of neurons that determine brain size. Most of the genetic causes of 'primary' developmental microcephaly (i.e., not associated with other syndromic features) are associated with centrosomal abnormalities. In addition to other functions, centrosomal proteins control the mitotic spindle, which is essential for normal cell proliferation during mitosis. However, the brain is often uniquely affected when microcephaly genes are mutated implying special centrosomal-related functions in neuronal production. Although models explaining how this could occur have some compelling data, they are not without controversy. Interestingly, some of the microcephaly genes show evidence that they were targets of evolutionary selection in primates and human ancestors, suggesting potential evolutionary roles in controlling neuronal number and brain volume across species. Mutations in DNA repair pathway genes also lead to microcephaly. Double-stranded DNA breaks appear to be a prominent type of damage that needs to be repaired during brain development, yet why defects in DNA repair affect the brain preferentially and if DNA repair relates to centrosome function, are not clearly understood.
对人类发育性小头畸形的研究为大脑发育提供了重要见解。现已明确，发育性小头畸形与细胞生成异常有关，而且小头畸形的病理生理学为大脑如何产生决定脑大小的适量神经元提供了显著的见解。“原发性”发育性小头畸形（即不伴有其他综合征特征）的大多数遗传病因都与中心体异常有关。除其他功能外，中心体蛋白控制有丝分裂纺锤体，这对有丝分裂期间的正常细胞增殖至关重要。然而，当小头畸形基因发生突变时，大脑往往会受到独特影响，这意味着在神经元生成过程中存在与中心体相关的特殊功能。尽管解释这种情况如何发生的模型有一些令人信服的数据，但并非没有争议。有趣的是，一些小头畸形基因显示出它们是灵长类动物和人类祖先进化选择的靶点的证据，这表明它们在控制跨物种神经元数量和脑容量方面可能具有进化作用。DNA修复途径基因的突变也会导致小头畸形。双链DNA断裂似乎是大脑发育过程中需要修复的一种突出的损伤类型，但为何DNA修复缺陷会优先影响大脑，以及DNA修复是否与中心体功能有关，目前尚不清楚。
