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J Biol Chem. 2015 Mar 20;290(12):7563-75. doi: 10.1074/jbc.M114.609487. Epub 2015 Jan 28.

Forkhead box F2 regulation of platelet-derived growth factor and myocardin/serum response factor signaling is essential for intestinal development.

Author information

1
From the Department of Pediatrics, Perinatal Institute, Cincinnati Children's Research Foundation, Cincinnati, Ohio 45229 and Craig.Bolte@cchmc.org.
2
From the Department of Pediatrics, Perinatal Institute, Cincinnati Children's Research Foundation, Cincinnati, Ohio 45229 and.
3
the Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
4
From the Department of Pediatrics, Perinatal Institute, Cincinnati Children's Research Foundation, Cincinnati, Ohio 45229 and Vladimir.Kalinichenko@cchmc.org.

Abstract

Alterations in the forkhead box F2 gene expression have been reported in numerous pathologies, and Foxf2(-/-) mice are perinatal lethal with multiple malformations; however, molecular mechanisms pertaining to Foxf2 signaling are severely lacking. In this study, Foxf2 requirements in murine smooth muscle cells were examined using a conditional knock-out approach. We generated novel Foxf2-floxed mice, which we bred to smMHC-Cre-eGFP mice to generate a mouse line with Foxf2 deleted specifically from smooth muscle. These mice exhibited growth retardation due to reduced intestinal length as well as inflammation and remodeling of the small intestine. Colons of Tg(smMHC-Cre-eGFP(+/-));Foxf2(-/-) mice had expansion of the myenteric nerve plexus and increased proliferation of smooth muscle cells leading to thickening of the longitudinal smooth muscle layer. Foxf2 deficiency in colonic smooth muscle was associated with increased expression of Foxf1, PDGFa, PDGFb, PDGF receptor α, and myocardin. FOXF2 bound to promoter regions of these genes indicating direct transcriptional regulation. Foxf2 repressed Foxf1 promoter activity in co-transfection experiments. We also show that knockdown of Foxf2 in colonic smooth muscle cells in vitro and in transgenic mice increased myocardin/serum response factor signaling and increased expression of contractile proteins. Foxf2 attenuated myocardin/serum response factor signaling in smooth muscle cells through direct binding to the N-terminal region of myocardin. Our results indicate that Foxf2 signaling in smooth muscle cells is essential for intestinal development and serum response factor signaling.

KEYWORDS:

Forkhead Protein; Foxf2; Gene Knockout; Intestine; Myocardin; Smooth Muscle; Transcription Factor; Transgenic Mice

PMID:
25631042
PMCID:
PMC4367262
DOI:
10.1074/jbc.M114.609487
[Indexed for MEDLINE]
Free PMC Article

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