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Updated: Apr 5, 2026
Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration
Published on: May 24, 2016
MEF2D deficiency in neonatal cardiomyocytes triggers cell cycle re-entry and programmed cell death in vitro
Nelsa L Estrella1, Amanda L Clark1, Cody A Desjardins1
1From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215.
Abstract:
The cardiomyocyte cell cycle is a poorly understood process. Mammalian cardiomyocytes permanently withdraw from the cell cycle shortly after birth but can re-enter the cell cycle and proliferate when subjected to injury within a brief temporal window in the neonatal period. Thus, investigating the mechanisms of cell cycle regulation in neonatal cardiomyocytes may provide critical insight into the molecular events that prevent adult myocytes from proliferating in response to injury or stress. MEF2D is a key transcriptional mediator of pathological remodeling in the adult heart downstream of various stress-promoting insults. However, the specific gene programs regulated by MEF2D in cardiomyocytes are unknown. By performing genome-wide transcriptome analysis using MEF2D-depleted neonatal cardiomyocytes, we found a significant impairment in the cell cycle, characterized by the up-regulation of numerous positive cell cycle regulators. Expression of Pten, the primary negative regulator of PI3K/Akt, was significantly reduced in MEF2D-deficient cardiomyocytes and found to be a direct target gene of MEF2D. Consistent with these findings mutant cardiomyocytes showed activation of the PI3K/Akt survival pathway. Paradoxically, prolonged deficiency of MEF2D in neonatal cardiomyocytes did not trigger proliferation but instead resulted in programmed cell death, which is likely mediated by the E2F transcription factor. These results demonstrate a critical role for MEF2D in cell cycle regulation of post-mitotic, neonatal cardiomyocytes in vitro.
Insights
Myocyte enhancer factor 2D (MEF2D) regulates neonatal cardiomyocyte cell cycle progression. MEF2D deficiency impairs cell cycle regulators, reduces PTEN, activates survival pathways, and paradoxically causes cell death.
Area of Science:
- Cardiovascular Biology
- Cell Cycle Regulation
- Molecular Cardiology
Background:
- Mammalian cardiomyocytes exit the cell cycle postnatally but can re-enter it in response to neonatal injury.
- Understanding neonatal cardiomyocyte cell cycle control offers insights into preventing adult myocyte proliferation.
- Myocyte enhancer factor 2D (MEF2D) is implicated in pathological cardiac remodeling but its role in cardiomyocyte cell cycle is unclear.
Purpose of the Study:
- To investigate the role of MEF2D in regulating the cell cycle of neonatal cardiomyocytes.
- To identify MEF2D-regulated genes involved in cardiomyocyte cell cycle control.
Main Methods:
- Genome-wide transcriptome analysis of MEF2D-depleted neonatal cardiomyocytes.
- Analysis of cell cycle regulators, PTEN expression, and PI3K/Akt pathway activation.
- Assessment of cardiomyocyte proliferation and programmed cell death.
Main Results:
- MEF2D depletion significantly impaired the cardiomyocyte cell cycle, upregulating positive cell cycle regulators.
- PTEN, a negative regulator of the PI3K/Akt pathway, was identified as a direct MEF2D target gene and its expression was reduced.
- MEF2D-deficient cardiomyocytes exhibited PI3K/Akt pathway activation but ultimately underwent programmed cell death, mediated by E2F.
Conclusions:
- MEF2D plays a critical role in regulating the cell cycle of post-mitotic neonatal cardiomyocytes.
- MEF2D controls cell cycle progression partly through regulating PTEN expression and the PI3K/Akt pathway.
- Dysregulation of MEF2D leads to cell cycle arrest and programmed cell death in neonatal cardiomyocytes.
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