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

Area of Science:

• Developmental Biology
• Molecular Genetics
• Gastroenterology

Background:

• Forkhead box F2 (Foxf2) gene alterations are linked to various pathologies.
• Foxf2 knockout mice exhibit perinatal lethality and malformations.
• Molecular mechanisms of Foxf2 signaling, particularly in smooth muscle, remain poorly understood.

Purpose of the Study:

• To investigate the role of Foxf2 in murine smooth muscle cells.
• To elucidate the molecular mechanisms by which Foxf2 regulates intestinal development and function.

Main Methods:

• Generation of novel Foxf2-floxed mice.
• Conditional knockout of Foxf2 specifically in smooth muscle using smMHC-Cre-eGFP mice.
• Analysis of intestinal morphology, gene expression, and protein signaling pathways in knockout mice and in vitro cell cultures.

Main Results:

• Foxf2 deficiency in smooth muscle led to growth retardation, reduced intestinal length, inflammation, and remodeling.
• Knockout mice showed an expanded myenteric nerve plexus and thickened longitudinal smooth muscle layer in the colon.
• Foxf2 deficiency increased expression of Foxf1, PDGF ligands and receptor, and myocardin, with direct binding of FOXF2 to regulatory regions.
• Foxf2 repressed Foxf1 promoter activity and attenuated myocardin/serum response factor signaling via direct binding to myocardin.

Conclusions:

• Foxf2 signaling in smooth muscle cells is essential for proper intestinal development.
• Foxf2 plays a critical role in regulating smooth muscle cell proliferation, differentiation, and function.
• Foxf2 acts as a repressor of key developmental and signaling pathways, including Foxf1 and myocardin/serum response factor signaling, in the intestinal smooth muscle.