Gene Expression Analyses during Spontaneous Reversal of Cardiomyopathy in Mice with Repressed Nuclear CUG-BP, Elav-Like Family (CELF) Activity in Heart Muscle.
Gene Expression Analyses during Spontaneous Reversal of Cardiomyopathy in Mice with Repressed Nuclear CUG-BP, Elav-Like Family (CELF) Activity in Heart Muscle.
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DOI：
10.1371/journal.pone.0124462
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ladd AN
中科院分区：
文献类型：
--
作者：
Dasgupta T;Coram RJ;Stillwagon SJ;Ladd AN
Cug-BP，Elav-like家族(CELF)蛋白调节心脏中细胞类型和发育阶段特异性的选择性剪接。先前研究表明，在MHC-CELFΔ转基因小鼠中，通过在心肌中表达核显性负性CELF蛋白来抑制CELf介导的剪接活性会导致选择性剪接的失调、心脏功能障碍、心肌肥厚和扩张性心肌病。一种表达较低水平显性负蛋白的MHC-CELFΔ小鼠在年轻时表现出心脏功能障碍和肌病，但随着年龄的增长自发恢复正常的心功能和心脏大小，尽管存在剪接缺陷。据我们所知，这是第一例不需要干预就能自动恢复的遗传性心肌病。在这项研究中，我们探索了这种复苏的基础。我们检测了在幼年MHC-CELFΔ小鼠中受血清反应因子调控的转录程序是否随着年龄的增长而恢复到温和的水平，并通过基因芯片分析评估了基因表达的整体变化。我们发现，在老年动物中，温和型和野生型心脏之间的基因表达差异大大减少，包括SRF靶基因表达的部分恢复。我们没有发现新的代偿途径随着年龄的增加而被激活的证据，并提出恢复可能是由于依赖CELF的剪接变体与心肌细胞的细胞环境的发育阶段特异性相容所致。
CUG-BP, Elav-like family (CELF) proteins regulate cell type- and developmental stage-specific alternative splicing in the heart. Repression of CELF-mediated splicing activity via expression of a nuclear dominant negative CELF protein in heart muscle was previously shown to induce dysregulation of alternative splicing, cardiac dysfunction, cardiac hypertrophy, and dilated cardiomyopathy in MHC-CELFΔ transgenic mice. A “mild” line of MHC-CELFΔ mice that expresses a lower level of the dominant negative protein exhibits cardiac dysfunction and myopathy at a young age, but spontaneously recovers normal cardiac function and heart size with age despite the persistence of splicing defects. To the best of our knowledge, this was the first example of a genetically induced cardiomyopathy that spontaneously recovers without intervention. In this study, we explored the basis for this recovery. We examined whether a transcriptional program regulated by serum response factor (SRF) that is dysregulated in juvenile MHC-CELFΔ mice is restored in the mild line with age, and evaluated global changes in gene expression by microarray analyses. We found that differences in gene expression between the mild line and wild type hearts are greatly reduced in older animals, including a partial recovery of SRF target gene expression. We did not find evidence of a new compensatory pathway being activated in the mild line with age, and propose that recovery may occur due to developmental stage-specific compatibility of CELF-dependent splice variants with the cellular environment of the cardiomyocyte.
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影响因子：
5
作者：
Haghighi K;Pritchard T;Bossuyt J;Waggoner JR;Yuan Q;Fan GC;Osinska H;Anjak A;Rubinstein J;Robbins J;Bers DM;Kranias EG
通讯作者：
Kranias EG
影响因子：
3.5
作者：
Ho, TH;Bundman, D;Cooper, TA
通讯作者：
Cooper, TA
DOI：
10.1073/pnas.85.2.339
发表时间：
1988-01-01
影响因子：
11.1
作者：
IZUMO, S;NADALGINARD, B;MAHDAVI, V
通讯作者：
MAHDAVI, V
影响因子：
20.1
作者：
Luo, WS;Wolska, BM;Kranias, EG
通讯作者：
Kranias, EG
影响因子：
18.2
作者：
Medin, Mania;Hermida-Prieto, Manuel;Castro-Beiras, Alfonso
通讯作者：
Castro-Beiras, Alfonso