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

Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, United States of America.
PLoS ONE (Impact Factor: 3.53). 07/2011; 6(7):e22217. DOI: 10.1371/journal.pone.0022217
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The alteration in proteome composition induced by environmental changes and various pathologies is accompanied by the modifications of proteins by specific co- and post-translational modifications (PTMs). The type and site stoichiometry of PTMs can affect protein functions, alter cell signaling and can have acute and chronic effects. The particular interest is drawn to those amino acid residues that can undergo several different PTMs. We hypothesize that these selected amino acid residues are biologically rare and act within the cell as molecular switches. There are, at least, twelve various lysine modifications currently known, several of them have been shown to be competitive and they influence the ability of a particular lysine to be modified by a different PTM. In this review, we discuss the PTMs that occur on lysine, specifically neddylation and sumoylation and the proteomic approaches that can be applied for the identification and quantification of these PTMs. Of interest are the emerging roles for these modifications in heart disease and what can be inferred from work in other cell types and organs. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    PROTEOMICS 03/2015; 15(5-6). DOI:10.1002/pmic.201400312 · 3.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rationale: In the mammalian heart, cardiomyocytes withdraw from the cell cycle and initiate hypertrophic growth soon after birth, but the transcriptional regulatory mechanisms that control these neonatal transitions are not well-defined. Objective: Forkhead family transcription factors have been implicated as positive (FoxM1) and negative (FoxO1 and FoxO3) regulators of cardiomyocyte proliferation prenatally, but their regulatory interactions and functions in neonatal cell cycle withdrawal have not been reported previously. Potential regulators of Fox activity, including the metabolic indicator AMP-activated protein kinase (AMPK), and Fox transcriptional targets (p21, p27, Insulin-like growth factor 1 (IGF1)) also were examined. Methods and Results: In cultured neonatal rat cardiomyocytes, AMPK activates FoxOs, and AMPK inhibition is sufficient to induce cell proliferation. In vivo, combined loss of FoxO1 and FoxO3 specifically in cardiomyocytes leads to delayed cell cycle withdrawal and increased expression of IGF1 and FoxM1. Conversely, cardiomyocyte-specific loss of FoxM1 results in decreased neonatal cardiomyocyte cell proliferation, decreased expression of IGF1, and increased expression of cell cycle inhibitors p21 and p27. IGF1 is a direct downstream target of cardiac Fox transcription factors, which is negatively regulated by FoxOs and positively regulated by FoxM1, dependent on AMPK activation status. Conclusions: These data support a regulatory mechanism whereby the balance of FoxO and FoxM1 transcription factors integrates metabolic status, mediated by AMPK, and cell cycle regulation, through competitive regulation of target genes including IGF1, in neonatal cardiomyocytes.
    Circulation Research 11/2012; 112(2). DOI:10.1161/CIRCRESAHA.112.277442 · 11.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pallister-Killian syndrome (PKS) is a sporadic multisystem genetic diagnosis characterized by facial dysmorphia, variable developmental delay and intellectual impairment, hypotonia, hearing loss, seizures, differences in skin pigmentation, temporal alopecia, diaphragmatic hernia, congenital heart defects, and other systemic abnormalities. Although congenital heart defects have been described in association with PKS, the full spectrum of heart disease is still not entirely known. Here, we describe the pattern of cardiac findings of 81 probands with PKS who have had at least one cardiac evaluation, demonstrating structural heart difference in 37% of our cohort (n = 30). Septal defects such as atrial or ventricular septal defects (n = 12) were the most commonly seen congenital heart differences. Additional findings included the occasional occurrence of bicuspid aortic valve, aortic dilatation, and cardiac hypertrophy/cardiomyopathy. We suggest cardiac evaluation for all individuals with PKS at the time of diagnosis as well as subsequent longitudinal follow-up to monitor for the development of cardiomyopathy and aortic dilatation. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 05/2014; 164(5). DOI:10.1002/ajmg.a.36413 · 2.30 Impact Factor

Full-text (4 Sources)

Available from
May 31, 2014