Science2014-06-13 5:16 PM

影响脑褶皱蛋白的新的基因突变 Evolutionarily Dynamic Alternative Splicing of GPR56 Regulates Regional Cerebral Cortical Patterning

论文摘要 

一项将某一特别基因与皮层脑回——即人脑表面显著的褶皱——挂钩的新研究提示,这些特征性的外形是以区段的方式形成并受到控制的。Byoung-il Bae及其同事对来自3个不同家族的5个人的基因组进行了研究,他们在布洛卡区——或大脑的语言中枢——有着异常薄且平滑的皮层脑回。研究人员发现,这5个人都在一个基因的调节部分,或“启动子”中含有某种基因变异;启动子是本身并不会编码任何蛋白但却会启动基因组其它部位基因表达的DNA序列。他们说,这个特别的基因突变会影响一个叫做GRP56的基因。因此,Bae及他的同事对人类胚胎组织及转基因小鼠的GRP56基因进行了研究并发现,GRP56的丧失会减缓在大脑中一个特定区域中神经祖细胞的产生,这些神经祖细胞就是即那些最终会成为神经元的细胞,而该基因的过度表达会使该区域中的这些祖细胞群增长。研究人员计划将这一突变添加至一个已知会引起异常皮层褶皱的因子名录中,希望它可被用于产前测试。据研究人员披露,他们的发现还可能有助于理解脑褶皱进化的历史。一篇由Brian Rash和Pasko Rakic撰写的《观点栏目》文章更为详细地重点介绍了这项研究及其意义。

Abstract 

The human neocortex has numerous specialized functional areas whose formation is poorly understood. Here, we describe a 15–base pair deletion mutation in a regulatory element of GPR56 that selectively disrupts human cortex surrounding the Sylvian fissure bilaterally including “Broca’s area,” the primary language area, by disrupting regional GPR56 expression and blocking RFX transcription factor binding. GPR56 encodes a heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor required for normal cortical development and is expressed in cortical progenitor cells. GPR56 expression levels regulate progenitor proliferation. GPR56 splice forms are highly variable between mice and humans, and the regulatory element of gyrencephalic mammals directs restricted lateral cortical expression. Our data reveal a mechanism by which control of GPR56 expression pattern by multiple alternative promoters can influence stem cell proliferation, gyral patterning, and, potentially, neocortex evolution.

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