title: Meis1 regulates postnatal cardiomyocyte cell cycle arrest.
abstract: The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by postnatal day 7 and the mechanisms of cardiomyocyte cell cycle arrest remain unclear. The homeodomain transcription factor Meis1 is required for normal cardiac development but its role in cardiomyocytes is unknown. Here we identify Meis1 as a critical regulator of the cardiomyocyte cell cycle. Meis1 deletion in mouse cardiomyocytes was sufficient for extension of the postnatal proliferative window of cardiomyocytes, and for re-activation of cardiomyocyte mitosis in the adult heart with no deleterious effect on cardiac function. In contrast, overexpression of Meis1 in cardiomyocytes decreased neonatal myocyte proliferation and inhibited neonatal heart regeneration. Finally, we show that Meis1 is required for transcriptional activation of the synergistic CDK inhibitors p15, p16 and p21. These results identify Meis1 as a critical transcriptional regulator of cardiomyocyte proliferation and a potential therapeutic target for heart regeneration.
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Ahmed I
authors.initials: AI
authors.lastname: Mahmoud
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Fatih
authors.initials: F
authors.lastname: Kocabas
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Shalini A
authors.initials: SA
authors.lastname: Muralidhar
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Wataru
authors.initials: W
authors.lastname: Kimura
authors.affiliation: School of Medicine, Ain Shams University, Cairo, 1156, Egypt.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Koura
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Suwannee
authors.initials: S
authors.lastname: Thet
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Enzo R
authors.initials: ER
authors.lastname: Porrello
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Hesham A
authors.initials: HA
authors.lastname: Sadek
mesh_terms: D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D006321:Heart / Q000033:anatomy & histology / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D015533:Transcriptional Activation
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins