Myocardium defects and ventricular hypoplasia in mice homozygous null for the Forkhead Box M1 transcription factor.
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 cardiomyocytes. 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 p21(Cip1) 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. Foxm1 regulates expression of genes essential for the proliferation of cardiomyocytes during heart development.
Ramakrishna
Sneha
S
Department of Medicine, University of Chicago, Chicago, Illinois.
Kim
Il-Man
IM
Petrovic
Vladimir
V
Malin
Dmitriy
D
Wang
I-Ching
IC
Kalin
Tanya V
TV
Meliton
Lucille
L
Zhao
You-Yang
YY
Ackerson
Timothy
T
Qin
Yimin
Y
Malik
Asrar B
AB
Costa
Robert H
RH
Kalinichenko
Vladimir V
VV
D000818:Animals; D009202:Cardiomyopathies / Q000151:congenital / Q000196:embryology / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D049109:Cell Proliferation; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication / Q000235:genetics; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics*; D006352:Heart Ventricles / Q000002:abnormalities* / Q000473:pathology; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D009206:Myocardium / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics; D011401:Promoter Regions, Genetic; D020687:cdc25 Phosphatases / Q000235:genetics
D018797:Cell Cycle Proteins; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D004247:DNA; D020687:cdc25 Phosphatases