Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency

English version

Autoři: Peiheng Gan ^aff001; Michaela Patterson ^aff004; Alexa Velasquez ^aff003; Kristy Wang ^aff001; Di Tian ^aff005; Jolene J. Windle ^aff006; Ge Tao ^aff001; Daniel P. Judge ^aff002; Takako Makita ^aff007; Thomas J. Park ^aff008; Henry M. Sucov ^aff001
Působiště autorů: Department of Regenerative Medicine and Cell Biology, Medical Univ. South Carolina, Charleston, South Carolina, United States of America ^aff001; Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, United States of America ^aff002; Department of Regenerative Medicine and Stem Cell Biology, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America ^aff003; Department of Cell Biology, Neurobiology and Anatomy, and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America ^aff004; Department of Pathology and Laboratory Medicine, Tulane Univeristy School of Medicine, New Orleans, Louisiana, United States of America ^aff005; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virgina, United States of America ^aff006; Darby Children’s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, United States of America ^aff007; Laboratory of Integrative Neuroscience, Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America ^aff008
Vyšlo v časopise: Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008354
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008354

Souhrn

Recent evidence implicates mononuclear diploid cardiomyocytes as a proliferative and regenerative subpopulation of the postnatal heart. The number of these cardiomyocytes is a complex trait showing substantial natural variation among inbred mouse strains based on the combined influences of multiple polymorphic genes. One gene confirmed to influence this parameter is the cardiomyocyte-specific kinase Tnni3k. Here, we have studied Tnni3k alleles across a number of species. Using a newly-generated kinase-dead allele in mice, we show that Tnni3k function is dependent on its kinase activity. In an in vitro kinase assay, we show that several common human TNNI3K kinase domain variants substantially compromise kinase activity, suggesting that TNNI3K may influence human heart regenerative capacity and potentially also other aspects of human heart disease. We show that two kinase domain frameshift mutations in mice cause loss-of-function consequences by nonsense-mediated decay. We further show that the Tnni3k gene in two species of mole-rat has independently devolved into a pseudogene, presumably associated with the transition of these species to a low metabolism and hypoxic subterranean life. This may be explained by the observation that Tnni3k function in mice converges with oxidative stress to regulate mononuclear diploid cardiomyocyte frequency. Unlike other studied rodents, naked mole-rats have a surprisingly high (30%) mononuclear cardiomyocyte level but most of their mononuclear cardiomyocytes are polyploid; their mononuclear diploid cardiomyocyte level (7%) is within the known range (2–10%) of inbred mouse strains. Naked mole-rats provide further insight on a recent proposal that cardiomyocyte polyploidy is associated with evolutionary acquisition of endothermy.

Klíčová slova:

Alleles – Mammalian genomics – Point mutation – Polyploidy – Sequence databases – In vitro kinase assay

Zdroje

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