J Neurogastroenterol Motil.
2015 Oct;21(4):589-602. 10.5056/jnm15063.
Serum Response Factor Is Essential for Prenatal Gastrointestinal Smooth Muscle Development and Maintenance of Differentiated Phenotype
- Affiliations
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- 1Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, USA. sro@medicine.nevada.edu
- 2Department of Physiology, Wonkwang Digestive Disease Research Institute and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan, Jeollabuk-do, Korea.
- 3Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
- 4Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA.
- KMID: 2381308
- DOI: http://doi.org/10.5056/jnm15063
Abstract
- BACKGROUND/AIMS
Smooth muscle cells (SMCs) characteristically express serum response factor (SRF), which regulates their development. The role of SRF in SMC plasticity in the pathophysiological conditions of gastrointestinal (GI) tract is less characterized.
METHODS
We generated SMC-specific Srf knockout mice and characterized the prenatally lethal phenotype using ultrasound biomicroscopy and histological analysis. We used small bowel partial obstruction surgeries and primary cell culture using cell-specific enhanced green fluorescent protein (EGFP) mouse lines to study phenotypic and molecular changes of SMCs by immunofluorescence, Western blotting, and quantitative polymerase chain reaction. Finally we examined SRF change in human rectal prolapse tissue by immunofluorescence.
RESULTS
Congenital SMC-specific Srf knockout mice died before birth and displayed severe GI and cardiac defects. Partial obstruction resulted in an overall increase in SRF protein expression. However, individual SMCs appeared to gradually lose SRF in the hypertrophic muscle. Cells expressing low levels of SRF also expressed low levels of platelet-derived growth factor receptor alpha (PDGFRalphalow) and Ki67. SMCs grown in culture recaptured the phenotypic switch from differentiated SMCs to proliferative PDGFRalphalow cells. The immediate and dramatic reduction of Srf and Myh11 mRNA expression confirmed the phenotypic change. Human rectal prolapse tissue also demonstrated significant loss of SRF expression.
CONCLUSIONS
SRF expression in SMCs is essential for prenatal development of the GI tract and heart. Following partial obstruction, SMCs down-regulate SRF to transition into proliferative PDGFRalphalow cells that may represent a phenotype responsible for their plasticity. These findings demonstrate that SRF also plays a critical role in the remodeling process following GI injury.
Keyword
MeSH Terms
-
Animals
Blotting, Western
Fluorescent Antibody Technique
Gastrointestinal Tract
Heart
Humans
Mice
Mice, Knockout
Microscopy, Acoustic
Muscle Cells
Muscle, Smooth*
Myocytes, Smooth Muscle
Parturition
Phenotype*
Plastics
Polymerase Chain Reaction
Primary Cell Culture
Receptors, Platelet-Derived Growth Factor
Rectal Prolapse
RNA, Messenger
Serum Response Factor*
Plastics
RNA, Messenger
Receptors, Platelet-Derived Growth Factor
Serum Response Factor
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