Meis1 regulates postnatal cardiomyocyte cell cycle arrest
The neonatal heart has a high regenerative capacity that is lost in adult life; the transcription factor Meis1 has been identified as a relevant proliferative switch for this transition, providing a potential therapeutic target for adult heart regeneration. Heart cells that keep on growing Adult mam...
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Published in | Nature (London) Vol. 497; no. 7448; pp. 249 - 253 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
09.05.2013
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | The neonatal heart has a high regenerative capacity that is lost in adult life; the transcription factor Meis1 has been identified as a relevant proliferative switch for this transition, providing a potential therapeutic target for adult heart regeneration.
Heart cells that keep on growing
Adult mammalian hearts cannot regenerate after injury, but neonatal mouse hearts can regenerate through cardiomyocyte proliferation until postnatal day 7, when the cells exit the cell cycle. Hesham Sadek and colleagues now provide insight into the mechanisms behind this transition. They show that the transcription factor Meis1 regulates the cardiomyocyte cell cycle, and that deletion of the
Meis1
gene in cardiomyocytes extends their postnatal proliferative window beyond 7 days. Conversely, overexpression of Meis1 inhibits neonatal mouse heart regeneration. These results demonstrate that the early postnatal cardiac regenerative window may hold the key to the potential of the adult mammalian heart to regenerate, and that Meis1 is a potential therapeutic target.
The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation
1
,
2
. 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
3
,
4
. 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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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/nature12054 |