Forkhead box F1 is essential for migration of mesenchymal cells and directly induces integrin-beta3 expression.
The Forkhead box f1 (Foxf1) transcription factor is expressed in mesenchymal cells of the lung, liver, and gallbladder. Although Foxf1 deficiency causes severe abnormalities in the development of these organs, the molecular mechanisms underlying Foxf1 function remain uncharacterized. In this study we inactivated Foxf1 function in lung mesenchymal cells and mouse embryonic fibroblasts (MEFs) by use of either short interfering RNA duplexes or a membrane-transducing Foxf1 dominant negative (DN) mutant protein (Foxf1 DN), the latter of which is fused to the human immunodeficiency virus TAT protein transduction domain. Although Foxf1 did not influence DNA replication or cell survival, Foxf1 depletion severely diminished mesenchyme migration. Foxf1 deficiency in mesenchymal cells was associated with reduced expression of the integrin-beta3 (Itgbeta3) subunit. Furthermore, we generated transgenic mice containing a tetracycline-inducible Foxf1 DN transgene. Adenovirus-mediated activation of Foxf1 DN in transgenic MEFs caused diminished cell migration and reduced Itgbeta3 expression. A chromatin immunoprecipitation assay demonstrated that Foxf1 protein binds to the bp -871 to -815 region of the mouse Itgbeta3 promoter. Deletion of the -871 to -815 Itgbeta3 promoter region completely abolished the ability of Foxf1 to activate transcription of the Itgbeta3 promoter in cotransfection experiments, indicating that the mouse Itgbeta3 is a direct transcriptional target of Foxf1 protein. Foxf1 plays an essential role in mesenchyme migration by transcriptionally regulating Itgbeta3.
Malin
Dmitriy
D
The University of Chicago, Division of the Biological Sciences, Department of Medicine, 5841 S. Maryland Ave., Chicago, IL 60637, USA.
Kim
Il-Man
IM
Boetticher
Evan
E
Kalin
Tanya V
TV
Ramakrishna
Sneha
S
Meliton
Lucille
L
Ustiyan
Vladimir
V
Zhu
Xiangdong
X
Kalinichenko
Vladimir V
VV
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002470:Cell Survival; D003001:Cloning, Molecular; D004261:DNA Replication; D051858:Forkhead Transcription Factors / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D039661:Integrin beta3 / Q000096:biosynthesis* / Q000235:genetics; D008648:Mesoderm / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; D039661:Integrin beta3