Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA
Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA
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DOI：
10.1073/pnas.1111780109
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发表时间：
2012-02-14
影响因子：
11.1
通讯作者：
Fong, Loren G.
中科院分区：
文献类型：
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作者：
Jung, Hea-Jin;Coffinier, Catherine;Fong, Loren G.
层状蛋白A和层状蛋白C是由LMNA基因拼接而成的，是核层的关键组成部分。这两种异构体在大多数组织中含量相似，但我们在大脑中观察到一种意想不到的表达模式。Western blot和免疫组化研究表明，lamin C在小鼠大脑中含量丰富，而lamin A及其前体prelamin A仅限于内皮细胞和脑膜细胞，在神经元和胶质细胞中不存在。Prelamin A在大脑中的转录水平较低，但这一发现不能用选择性剪接来解释。在只敲入层粘胶蛋白A的小鼠中，没有选择性剪接，所有基因的输出都被引导到层粘胶蛋白A前转录物中，在外周组织中发现了大量的层粘胶蛋白A，但在大脑中发现的层粘胶蛋白A很少。此外，在只表达progerin（一种在Hutchinson-Gilford早衰综合征中发现的有毒形式的prelamin a）的敲除蛋白小鼠中，大脑中的progerin水平极低。进一步的研究表明，脑特异性microRNA miR-9下调了prelamin A的表达，而不是lamin C的表达。培养细胞中miR-9的表达降低了层粘连蛋白A的表达，当层粘连蛋白A 3' UTR中的miR-9结合位点发生突变时，这种作用被消除。大脑中prelamin A表达的下调可以解释为什么Hutchinson-Gilford早衰综合征小鼠模型没有中枢神经系统病理。
Lamins A and C, alternatively spliced products of the LMNA gene, are key components of the nuclear lamina. The two isoforms are found in similar amounts in most tissues, but we observed an unexpected pattern of expression in the brain. Western blot and immunohistochemistry studies showed that lamin C is abundant in the mouse brain, whereas lamin A and its precursor prelamin A are restricted to endothelial cells and meningeal cells and are absent in neurons and glia. Prelamin A transcript levels were low in the brain, but this finding could not be explained by alternative splicing. In lamin A-only knockin mice, where alternative splicing is absent and all the output of the gene is channeled into prelamin A transcripts, large amounts of lamin A were found in peripheral tissues, but there was very little lamin A in the brain. Also, in knockin mice expressing exclusively progerin (a toxic form of prelamin A found in Hutchinson-Gilford progeria syndrome), the levels of progerin in the brain were extremely low. Further studies showed that prelamin A expression, but not lamin C expression, is down-regulated by a brain-specific microRNA, miR-9. Expression of miR-9 in cultured cells reduced lamin A expression, and this effect was abolished when the miR-9-binding site in the prelamin A 3' UTR was mutated. The down-regulation of prelamin A expression in the brain could explain why mouse models of Hutchinson-Gilford progeria syndrome are free of central nervous system pathology.