Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling
Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling
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DOI：
10.1073/pnas.2008861118
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发表时间：
2021-01-12
影响因子：
11.1
通讯作者：
Pu, William T.
中科院分区：
文献类型：
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作者：
Guo, Yuxuan;Cao, Yangpo;Pu, William T.
缺乏有关心肌细胞成熟的知识是心脏再生医学的一个主要瓶颈。在发育过程中，心肌细胞成熟的特征是主要发生在围产期的精心安排的结构、转录和功能特化。肌节是调节其他细胞器超微结构成熟的关键细胞骨架结构，但肌节是否调节心肌细胞成熟所必需的信号转导途径仍不清楚。为了解决这个问题，在这里，我们产生了心肌细胞特异性，马赛克，和α-辅肌动蛋白-2（Actn 2）的亚型突变的小鼠，以研究肌节在出生后心肌细胞成熟中的细胞自主作用。Actn 2突变导致横小管和线粒体结构成熟缺陷。此外，Actn 2突变引发转录失调，包括关键肌节和线粒体基因的异常表达，以及成熟基因表达的正常进展的严重损害。从机制上讲，Actn 2突变心肌细胞中的转录变化与血清反应因子（SRF）缺失的心肌细胞中的转录变化密切相关，SRF是一种调节心肌细胞成熟的关键转录因子。Actn 2突变增加了心脏α-肌动蛋白的单体形式，其与SRF辅因子MRTFA相互作用并扰乱其核定位。显性阴性MRTFA突变体的过表达足以概括Actn 2和Srf突变心肌细胞中的形态和转录缺陷。总之，这些数据表明，基于Actn 2的肌节组织通过MRTF-SRF信号传导调节心肌细胞的结构和转录成熟。
The paucity of knowledge about cardiomyocyte maturation is a major bottleneck in cardiac regenerative medicine. In development, cardiomyocyte maturation is characterized by orchestrated structural, transcriptional, and functional specializations that occur mainly at the perinatal stage. Sarcomeres are the key cytoskeletal structures that regulate the ultrastructural maturation of other organelles, but whether sarcomeres modulate the signal transduction pathways that are essential for cardiomyocyte maturation remains unclear. To address this question, here we generated mice with cardiomyocyte-specific, mosaic, and hypomorphic mutations of alpha-actinin-2 (Actn2) to study the cell-autonomous roles of sarcomeres in postnatal cardiomyocyte maturation. Actn2 mutation resulted in defective structural maturation of transverse-tubules and mitochondria. In addition, Actn2 mutation triggered transcriptional dysregulation, including abnormal expression of key sarcomeric and mitochondrial genes, and profound impairment of the normal progression of maturational gene expression. Mechanistically, the transcriptional changes in Actn2 mutant cardiomyocytes strongly correlated with those in cardiomyocytes deleted of serum response factor (SRF), a critical transcription factor that regulates cardiomyocyte maturation. Actn2 mutation increased the monomeric form of cardiac a-actin, which interacted with the SRF cofactor MRTFA and perturbed its nuclear localization. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the morphological and transcriptional defects in Actn2 and Srf mutant cardiomyocytes. Together, these data indicate that Actn2-based sarcomere organization regulates structural and transcriptional maturation of cardiomyocytes through MRTF-SRF signaling.