Myocardium defects and ventricular hypoplasia in mice homozygous null for the Forkhead Box M1 transcription factor

Sneha Ksmiakrishna, Il-man Kim, Vladimir Petrovic, Dmitriy Malin, I. Ching Wang, Tanya V. Kalin, Lucille Meliton, You Yang Zhao, Timothy Ackerson, Yimin Qin, Asrar B. Malik, Robert H. Costa, Vladimir V. Kalinichenko

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

The Forkhead Box m1 (Foxm1) transcription factor is expressed in cardiomyocytes and cardiac endothelial cells during heart development. In this study, we used a novel Foxm1 -/- mouse line to demonstrate that Foxm1-deletion causes ventricular hypoplasia and diminished DNA replication and mitosis in developing cardioniyocytes. Proliferation defects in Foxm1 -/- hearts were associated with a reduced expression of Cdk1-activator Cdc25B phosphatase and NFATc3 transcription factor, and with abnormal nuclear accumulation of the Cdk-inhibitor p21Cip1 protein. Depletion of Foxm1 levels by siRNA caused altered expression of these genes in cultured HL-1 cardiomyocytes. Endothelial-specific deletion of the Foxm1 fl/fl allele in Tie2-Cre Foxm1 fl/fl embryos did not influence heart development and cardiomyocyte proliferation. Foxm1 protein binds to the -9,259/-9,288-bp region of the endogenous mouse NFATc3 promoter, indicating that Foxm1 is a transcriptional activator of the NFATc3 gene. Foxinl regulates expression of genes essential for the proliferation of cardioniyocytes during heart development.

Original languageEnglish (US)
Pages (from-to)1000-1013
Number of pages14
JournalDevelopmental Dynamics
Volume236
Issue number4
DOIs
StatePublished - Apr 1 2007

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Keywords

  • Cardiomyocyte
  • Forkhead transcription factor
  • Heart development
  • Knockout mice
  • NFATc3
  • Trident
  • Winged helix DNA binding domain
  • p21

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Ksmiakrishna, S., Kim, I., Petrovic, V., Malin, D., Wang, I. C., Kalin, T. V., Meliton, L., Zhao, Y. Y., Ackerson, T., Qin, Y., Malik, A. B., Costa, R. H., & Kalinichenko, V. V. (2007). Myocardium defects and ventricular hypoplasia in mice homozygous null for the Forkhead Box M1 transcription factor. Developmental Dynamics, 236(4), 1000-1013. https://doi.org/10.1002/dvdy.21113