Genetic causes of microcephaly and lessons for neuronal development.
Genetic causes of microcephaly and lessons for neuronal development.
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DOI：
10.1002/wdev.89
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发表时间：
2013-07
影响因子：
--
通讯作者：
Walsh, Christopher A.
中科院分区：
文献类型：
--
作者：
Gilmore, Edward C.;Walsh, Christopher A.
人类发育性小头畸形的研究为大脑发育提供了重要的见解。已经很清楚，发育性小头畸形与细胞产生异常有关，并且小头畸形的病理生理学为大脑如何产生决定大脑大小的适当数量的神经元提供了显着的见解。“原发性”发育性小头畸形的大多数遗传原因（即，与其他综合征特征无关）与中心体异常有关。除了其他功能外，中心体蛋白还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，当小头畸形基因突变时，大脑往往受到独特的影响，这意味着神经元产生中的特殊中心体相关功能。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，但它们并非没有争议。有趣的是，一些小头畸形基因显示出证据，表明它们是灵长类动物和人类祖先进化选择的目标，这表明它们在控制不同物种的神经元数量和脑容量方面具有潜在的进化作用。DNA修复途径基因的突变也会导致小头畸形。双链DNA断裂似乎是一种重要的损伤类型，需要在大脑发育过程中修复，但为什么DNA修复缺陷优先影响大脑，以及DNA修复是否与中心体功能有关，尚不清楚。
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.