title: Myocardium defects and ventricular hypoplasia in mice homozygous null for the Forkhead Box M1 transcription factor.
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 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.
authors: Department of Medicine, University of Chicago, Chicago, Illinois.
authors: Sneha
authors: S
authors: Ramakrishna
authors: Il-Man
authors: IM
authors: Kim
authors: Vladimir
authors: V
authors: Petrovic
authors: Dmitriy
authors: D
authors: Malin
authors: I-Ching
authors: IC
authors: Wang
authors: Tanya V
authors: TV
authors: Kalin
authors: Lucille
authors: L
authors: Meliton
authors: You-Yang
authors: YY
authors: Zhao
authors: Timothy
authors: T
authors: Ackerson
authors: Yimin
authors: Y
authors: Qin
authors: Asrar B
authors: AB
authors: Malik
authors: Robert H
authors: RH
authors: Costa
authors: Vladimir V
authors: VV
authors: Kalinichenko
mesh_terms: 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
chemical_list: 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