miR-15 family regulates postnatal mitotic arrest of cardiomyocytes

Porrello, Enzo R., Johnson, Brett A., Aurora, Arin B., Simpson, Emma, Nam, Young-Jae, Matkovich, Scot J., Dorn, Gerald W., II, van Rooij, Eva and Olson, Eric N. (2011) miR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circulation Research, 109 6: 670-679. doi:10.1161/CIRCRESAHA.111.248880


Author Porrello, Enzo R.
Johnson, Brett A.
Aurora, Arin B.
Simpson, Emma
Nam, Young-Jae
Matkovich, Scot J.
Dorn, Gerald W., II
van Rooij, Eva
Olson, Eric N.
Title miR-15 family regulates postnatal mitotic arrest of cardiomyocytes
Journal name Circulation Research   Check publisher's open access policy
ISSN 0009-7330
1524-4571
Publication date 2011-09-01
Sub-type Article (original research)
DOI 10.1161/CIRCRESAHA.111.248880
Volume 109
Issue 6
Start page 670
End page 679
Total pages 10
Place of publication Baltimore, MD, United States
Publisher Lippincott Williams & Wilkins
Language eng
Formatted abstract
Rationale: Mammalian cardiomyocytes withdraw from the cell cycle during early postnatal development, which significantly limits the capacity of the adult mammalian heart to regenerate after injury. The regulatory mechanisms that govern cardiomyocyte cell cycle withdrawal and binucleation are poorly understood.
Objective: Given the potential of microRNAs (miRNAs) to influence large gene networks and modify complex developmental and disease phenotypes, we searched for miRNAs that were regulated during the postnatal switch to terminal differentiation.
Methods and Results: Microarray analysis revealed subsets of miRNAs that were upregulated or downregulated in cardiac ventricles from mice at 1 and 10 days of age (P1 and P10). Interestingly, miR-195 (a member of the miR-15 family) was the most highly upregulated miRNA during this period, with expression levels almost 6-fold higher in P10 ventricles relative to P1. Precocious overexpression of miR-195 in the embryonic heart was associated with ventricular hypoplasia and ventricular septal defects in β-myosin heavy chain–miR-195 transgenic mice. Using global gene profiling and argonaute-2 immunoprecipitation approaches, we showed that miR-195 regulates the expression of a number of cell cycle genes, including checkpoint kinase 1 (Chek1), which we identified as a highly conserved direct target of miR-195. Finally, we demonstrated that knockdown of the miR-15 family in neonatal mice with locked nucleic acid–modified anti-miRNAs was associated with an increased number of mitotic cardiomyocytes and derepression of Chek1.
Keyword miR-195
Neonate
Cell cycle
Binucleation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
 
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