Loss of serum response factor induces microRNA-mediated apoptosis in intestinal smooth muscle cells.

C Park,T J Yu,J M Miano,R M Berent,S Ro,O J Slivano,R Fuchs,M Y Lee,K M Sanders,J K Park,P J Park,S Ha,N C Collins,H Syn,K Horiguchi

doi:10.1038/cddis.2015.353

Abstract

Serum response factor (SRF) is a transcription factor known to mediate phenotypic plasticity in smooth muscle cells (SMCs). Despite the critical role of this protein in mediating intestinal injury response, little is known about the mechanism through which SRF alters SMC behavior. Here, we provide compelling evidence for the involvement of SRF-dependent microRNAs (miRNAs) in the regulation of SMC apoptosis. We generated SMC-restricted Srf inducible knockout (KO) mice and observed both severe degeneration of SMCs and a significant decrease in the expression of apoptosis-associated miRNAs. The absence of these miRNAs was associated with overexpression of apoptotic proteins, and we observed a high level of SMC death and myopathy in the intestinal muscle layers. These data provide a compelling new model that implicates SMC degeneration via anti-apoptotic miRNA deficiency caused by lack of SRF in gastrointestinal motility disorders.

Highlights

Box sequence [CC (A/T)[6] GG] in promoters and introns of most smooth muscle cells (SMCs)-restricted genes.[1]
MYOCD, which is an integral part of the Serum response factor (SRF)/myocardin-related transcription factors (MRTFs) pathway, has been recently implicated in apoptosis and autophagy of SMCs,[7] and SRF has been shown to attenuate Myc-induced apoptosis in mammary epithelial cells in culture.[8]
Srf gene mutageneses in mice result in severe defects in gastrulation,[14] and heart development as well as in GI tract development (SMC-specific Myh[11] promoter-driven KO).[13]

Summary

Introduction

Box sequence [CC (A/T)[6] GG] in promoters and introns of most SMC-restricted genes.[1]. MKL2, directly interact with SRF to activate a subset of SRF-modulated genes to promote myogenic differentiation and cytoskeletal structuring.[3] SRF is known primarily as the critical switch for induction of the muscle phenotype, it has recently been implicated in more diverse and multifunctional roles. Our proposed model reveals how loss of SRF expression can lead to SMC death and intestinal myopathy in the development of GI motility disorders

Methods

Results

Conclusion