Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency


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): e1008354. doi:10.1371/journal.pgen.1008354
Kategorie: Research Article
doi: 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 – Cardiomyocytes – Heart – Mammalian genomics – Point mutation – Polyploidy – Sequence databases – In vitro kinase assay


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Genetika Reprodukční medicína

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PLOS Genetics


2019 Číslo 10

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