The transcription factor Foxf1 binds to serum response factor and myocardin to regulate gene transcription in visceral smooth muscle cells.
Smooth muscle cells (SMCs) modulate their phenotype from a quiescent contractile state to a dedifferentiated, proliferative and migratory state during the pathogenesis of many diseases, including intestinal pseudoobstruction. Understanding how smooth muscle gene expression is regulated in these different phenotypic states is critical for unraveling the pathogenesis of these diseases. In the current study we examined the specific roles of Foxf1 in visceral SMC differentiation. Data show that Foxf1 is specifically required for expression of several contractile and regulatory proteins such as telokin, smooth muscle γ-actin, and Cav1.2b in visceral SMCs. Mechanistically, Foxf1 directly binds to and activates the telokin promoter. Foxf1 also directly binds to serum response factor (SRF) and myocardin-related transcription factors (MRTFs). Unlike Foxo4 and Foxq1, which bind to MRTFs and block their interaction with SRF, Foxf1 acts synergistically with these proteins to regulate telokin expression. Knock-out of Foxf1 specifically in SMCs results in neonatal lethality, with mice exhibiting GI tract abnormalities. Mice heterozygous for Foxf1 in SMC exhibited impaired colonic contractility and decreased expression of contractile proteins. These studies together with previous studies, suggest that different forkhead proteins can regulate gene expression in SMCs through modulating the activity of the SRF-myocardin axis to either promote or inhibit differentiation and proliferation thereby altering gastrointestinal contractility and development.
From the Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202 and.
April M
AM
Hoggatt
Ju-Ryoung
JR
Kim
Vladimir
V
Ustiyan
Xiaomeng
X
Ren
Tanya V
TV
Kalin
Vladimir V
VV
Kalinichenko
B Paul
BP
Herring
D020856:AT Rich Sequence / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D026362:Serum Response Factor / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014781:Viscera / Q000166:cytology*; D000099251:Myocardin
D003285:Contractile Proteins; D051858:Forkhead Transcription Factors; D009219:Myosin-Light-Chain Kinase; D009687:Nuclear Proteins; D010446:Peptide Fragments; D026362:Serum Response Factor; D015534:Trans-Activators; D000099251:Myocardin; C486293:Foxf1 protein, mouse; C107579:Foxq1 protein, mouse; C060640:telokin
Forkhead Factors; Gene Knockout; Gene Regulation; Gene Transcription; Smooth Muscle; Transcription/Developmental Factors; telokin