气候变化领域集成服务门户(CCPortal): Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling

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DOI	10.1073/pnas.2008861118
	Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling
	Guo Y.; Cao Y.; Jardin B.D.; Sethi I.; Ma Q.; Moghadaszadeh B.; Troiano E.C.; Mazumdar N.; Trembley M.A.; Small E.M.; Yuan G.-C.; Beggs A.H.; Pu W.T.
发表日期	2021
ISSN	00278424
卷号	118 期号:2
英文摘要	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 α-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 α-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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Actinin 2; Cardiomyocyte maturation; Cardiomyopathy; MRTF; SRF
语种	英语
scopus关键词	alpha actinin 2; myocardin; myocardin related transcription factor A; serum response factor; transcription factor; unclassified drug; Actn2 gene; animal tissue; Article; cardiac muscle cell; cell maturation; controlled study; gene expression; gene mutation; genetic transcription; heart mitochondrion; mouse; nonhuman; priority journal; protein localization; protein protein interaction; sarcomere; signal transduction; transverse tubular system
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181092
作者单位	Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, United States; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, United States; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States; Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642, United States; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, United States
推荐引用方式 GB/T 7714	Guo Y.,Cao Y.,Jardin B.D.,et al. Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling[J],2021,118(2).
APA	Guo Y..,Cao Y..,Jardin B.D..,Sethi I..,Ma Q..,...&Pu W.T..(2021).Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling.Proceedings of the National Academy of Sciences of the United States of America,118(2).
MLA	Guo Y.,et al."Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling".Proceedings of the National Academy of Sciences of the United States of America 118.2(2021).