Cited by 83Congenital heart defects researchDevelopmental Biology and Gene RegulationCardiac electrophysiology and arrhythmias

Expression of Foxm1 Transcription Factor in Cardiomyocytes Is Required for Myocardial Development

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Bolte, Craig, Zhang, Yufang, Wang, I-Ching, Kalin, Tanya V., Molkentin, Jeffrey D., Kalinichenko, Vladimir V.·2011·PLoS ONE

Abstract

Forkhead Box M1 (Foxm1) is a transcription factor essential for organ morphogenesis and development of various cancers. Although complete deletion of Foxm1 in Foxm1(-/-) mice caused embryonic lethality due to severe abnormalities in multiple organ systems, requirements for Foxm1 in cardiomyocytes remain to be determined. This study was designed to elucidate the cardiomyocyte-autonomous role of Foxm1 signaling in heart development. We generated a new mouse model in which Foxm1 was specifically deleted from cardiomyocytes (Nkx2.5-Cre/Foxm1(fl/f) mice). Deletion of Foxm1 from cardiomyocytes was sufficient to disrupt heart morphogenesis and induce embryonic lethality in late gestation. Nkx2.5-Cre/Foxm1(fl/fl) hearts were dilated with thinning of the ventricular walls and interventricular septum, as well as disorganization of the myocardium which culminated in cardiac fibrosis and decreased capillary density. Cardiomyocyte proliferation was diminished in Nkx2.5-Cre/Foxm1(fl/fl) hearts owing to altered expression of multiple cell cycle regulatory genes, such as Cdc25B, Cyclin B(1), Plk-1, nMyc and p21(cip1). In addition, Foxm1 deficient hearts displayed reduced expression of CaMKIIδ, Hey2 and myocardin, which are critical mediators of cardiac function and myocardial growth. Our results indicate that Foxm1 expression in cardiomyocytes is critical for proper heart development and required for cardiomyocyte proliferation and myocardial growth.

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  • Among the top 25 deleted genes with the most significant effect were transcription factors known to regulate myocardial development (e.g. FOXM1) and entirely novel dosage-sensitive gene candidates such as TEAD4.

    “Among the top 25 deleted genes with the most significant effect were transcription factors known to regulate myocardial development (e.g. FOXM125,26) and entirely novel dosage-sensitive gene candidates such as TEAD4 (Supplementary Table 3).”

    From Transfer learning enables predictions in network biology (2023) · cites this paper as [25]

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Authors
Bolte, C., Zhang, Y., Wang, I.-C., Kalin, T. V., Molkentin, J. D., & Kalinichenko, V. V.
Affiliations
Cincinnati Children's Hospital Medical Center (US)
Corresponding author
  • Bolte, Craig
  • Kalinichenko, Vladimir V.
Venue
PLoS ONE
Published
2011-07-14
Volume
6
Issue
7
Pages
e22217
ISSN
1932-6203 (ISSN-L)
OpenAlex
W1969661970
Cited by
83
References
46
Citations by year
2026: 4 · 2025: 7 · 2024: 6 · 2023: 5 · 2022: 12 · 2021: 9 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 6 · 2016: 5 · 2015: 4 · 2014: 4 · 2013: 1 · 2012: 5
FWCI
1.30
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Heart, Lung, and Blood Institute (HL 84151-04, R01HL084151)
  • National Cancer Institute (R01CA142724)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
FOXM1, cardiomyocytes, heart development, cardiomyocyte proliferation, myocardial fibrosis, cell cycle regulation, embryonic lethality, CaMKIIδ, Hey2, myocardin
MeSH terms
Forkhead Box Protein M1, Polo-Like Kinase 1, Animals, Heart, Immunohistochemistry, Myocardium, Proto-Oncogene Proteins, Blotting, Western, Protein Serine-Threonine Kinases, Mice, Knockout, Gene Expression Regulation, Developmental, Cell Cycle Proteins, Reverse Transcriptase Polymerase Chain Reaction, cdc25 Phosphatases, Myocytes, Cardiac, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Mice, Forkhead Transcription Factors, Cyclin B1

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