Bcl-x Pre-mRNA splicing regulates brain injury after neonatal hypoxia-ischemia

Qingli Xiao, Andria L. Ford, Jan Xu, Ping Yan, Kuang Yung Lee, Ernesto Gonzales, Tim West, David M. Holtzman, Jin Moo Lee*

*此作品的通信作者

研究成果: 期刊稿件文章同行評審

17 引文 斯高帕斯(Scopus)

摘要

The bcl-x gene appears to play a critical role in regulating apoptosis in the developing and mature CNS and following CNS injury. Two isoforms of Bcl-x are produced as a result of alternative pre-mRNA splicing: Bcl-xL (the long form) is anti-apoptotic, while Bcl-xS (short form) is pro-apoptotic. Despite the antagonistic activities of these two isoforms, little is known about how regulation of alternative splicing of bcl-x may mediate neural cell apoptosis. Here, we report that apoptotic stimuli (staurosporine or C2-ceramide) reciprocally altered Bcl-x splicing in neural cells, decreasing Bcl-xL while increasing Bcl-xS. Specific knockdown of Bcl-xS attenuated apoptosis. To further define regulatory elements that influenced Bcl-x splicing, a Bcl-x minigene was constructed. Deletional analysis revealed several consensus sequences within intron 2 that altered splicing.Wefound that the splicing factor, CUG-binding-protein-1 (CUGBP1), bound to a consensus sequence close to the Bcl-xL 5′ splice site, altering the Bcl-xL /Bcl-xS ratio and influencing cell death. In vivo, neonatal hypoxia-ischemia reciprocally altered Bcl-x pre-mRNA splicing, similar to the in vitro studies. Manipulation of the splice isoforms using viral gene transfer of Bcl-xS shRNA into the hippocampus of rats before neonatal hypoxia-ischemia decreased vulnerability to injury. Moreover, alterations in nuclear CUGBP1 preceded Bcl-x splicing changes. These results suggest that alternative pre-mRNA splicing may be an important regulatory mechanism for cell death after acute neurological injury and may potentially provide novel targets for intervention.

原文英語
頁(從 - 到)13587-13596
頁數10
期刊Journal of Neuroscience
32
發行號39
DOIs
出版狀態已出版 - 26 09 2012
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