Meis1 regulates postnatal cardiomyocyte cell cycle arrest

1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2].
Nature (Impact Factor: 41.46). 04/2013; 497(7448). DOI: 10.1038/nature12054
Source: PubMed


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.

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Available from: Ahmed I Mahmoud
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    • "2011 ) ( Wang et al . , 2011 ) ( Schnabel et al . , 2011 ) ( Oberpriller and Oberpriller 1974 ) ( Witman et al . , 2011 ) ( Porrello et al . , 2011 ) ( Porrello et al . , 2013 ) ( Mahmoud et al . , 2014 ) ( Mahmoud et al . , 2013 ) ( Darehzereshki et al . , 2014 ) ( Porrello et al . , 2011 ) ( Porrello et al . , 2013 ) ( Mahmoud et al . , 2014 ) ( Mahmoud et al . , 2013 ) ( Kajstura et al . , 2010 ) ( Canseco et al . , 2015 ) heart . When this procedure was performed in zebrafish , it led to heart regeneration over a longer time period ( more than 130 days ) ( Chablais et al . , 2011 ; González - Rosa et al . , 2011 ) . Wang et al . ( 2011 ) applied a genetic ablation injury to extrapolate the regenera"

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    • "Quantification of the pH3 positive cardiomyocytes showed a significant decrease in the number of proliferating cardiomyocytes in resected plus vagotomized mice compared to resection alone (Figure S2B, n = 5, p < 0.05). Similar to regeneration following apical resection, neonatal mice have the capacity to regenerate their hearts following myocardial infarction (MI), a major cause of heart failure in humans (Mahmoud et al., 2014; Porrello et al., 2013). We performed both MI + vagotomy on 1-day-old mice (Figure 4A). "
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    ABSTRACT: Some organisms, such as adult zebrafish and newborn mice, have the capacity to regenerate heart tissue following injury. Unraveling the mechanisms of heart regeneration is fundamental to understanding why regeneration fails in adult humans. Numerous studies have revealed that nerves are crucial for organ regeneration, thus we aimed to determine whether nerves guide heart regeneration. Here, we show using transgenic zebrafish that inhibition of cardiac innervation leads to reduction of myocyte proliferation following injury. Specifically, pharmacological inhibition of cholinergic nerve function reduces cardiomyocyte proliferation in the injured hearts of both zebrafish and neonatal mice. Direct mechanical denervation impairs heart regeneration in neonatal mice, which was rescued by the administration of neuregulin 1 (NRG1) and nerve growth factor (NGF) recombinant proteins. Transcriptional analysis of mechanically denervated hearts revealed a blunted inflammatory and immune response following injury. These findings demonstrate that nerve function is required for both zebrafish and mouse heart regeneration. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Developmental Cell
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    • "Genome-wide association studies have also found an association of Meis1 with Restless Legs Syndrome (Spieler et al., 2014; Winkelmann et al., 2007) and cardiac conduction defects (Butler et al., 2012; Pfeufer et al., 2010; Smith et al., 2011). Recently, Meis1 was found to be implicated in cardiomyocyte differentiation (Wamstad et al., 2012) and in the control of proliferation of post-natal myocardium (Mahmoud et al., 2013). Several mouse models with targeted mutations in the Meis1 locus have been described. "
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    ABSTRACT: Meis1 is a highly conserved transcription factor that is activated in a regionally restricted manner from early stages of development. Meis1 belongs to the three amino acid loop extension (TALE) homeodomain family. Together with Pbx1, Meis1 plays a major role as a Hox cofactor and therefore plays an essential role in the development of several embryonic organs and systems, including limbs, heart, blood and vasculature. In addition Meis1 is required for the development of Hox-free embryonic regions and interacts with non-Hox homeodomain and non-homeodomain transcription factors. During postnatal life Meis1 is involved in adult cardiomyocyte homeostasis and has been associated with predisposition to human neural and cardiac pathologies. Given the relevance of this transcription factor, we have developed two new Meis1 gene knockin models; a direct ECFP knockin insertion that allows the direct identification of Meis1-expressing cells in living tissues, and a CreERT2 insertion that allows the inducible genetic tracing of Meis1-expressing cells in a time-controlled manner. Importantly, these two alleles represent the first Meis1 mutations in which Meis1 protein production is completely eliminated. These newly targeted Meis1 alleles will be valuable tools to further our understanding of the role of this critical transcription factor during development and disease. © 2014 Wiley Periodicals, Inc.
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