Publication Date:
2013-04-19
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159712/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159712/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mahmoud, Ahmed I -- Kocabas, Fatih -- Muralidhar, Shalini A -- Kimura, Wataru -- Koura, Ahmed S -- Thet, Suwannee -- Porrello, Enzo R -- Sadek, Hesham A -- 1R01HL115275-01/HL/NHLBI NIH HHS/ -- R01 HL115275/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 May 9;497(7448):249-53. doi: 10.1038/nature12054. Epub 2013 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23594737" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Animals
;
Animals, Newborn
;
*Cell Cycle Checkpoints
;
Cell Proliferation
;
Cyclin-Dependent Kinase Inhibitor p15/metabolism
;
Cyclin-Dependent Kinase Inhibitor p16/metabolism
;
Cyclin-Dependent Kinase Inhibitor p21/metabolism
;
Female
;
Heart/anatomy & histology/physiology
;
Homeodomain Proteins/genetics/*metabolism
;
Male
;
Mice
;
Myocardial Infarction/metabolism/pathology
;
Myocytes, Cardiac/*cytology/*metabolism
;
Neoplasm Proteins/deficiency/genetics/*metabolism
;
Regeneration
;
Transcriptional Activation
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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