Inducible Mouse Model of Chronic Intestinal Pseudo-Obstruction by Smooth Muscle-Specific Inactivation of the SRF Gene

Mericskay, Mathias; Blanc, Jocelyne; Tritsch, Eva; Moriez, Raphaël; Aubert, P.; Neunlist, Michel; Feil, Robert; Li, Zhenlin

doi:10.1053/j.gastro.2007.09.010

Cited by 51 publications

(61 citation statements)

References 30 publications

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“…70,71 This phenotype is characterized by loss of intestinal peristalsis due to defective SMC contractility. Predictably, inactivation of SRF resulted in attenuated levels of several SMC contractile genes in both the colon and the duodenum.…”

Section: Gastrointestinal Tractmentioning

confidence: 99%

Role of serum response factor in the pathogenesis of disease

Miano

2010

Laboratory Investigation

119

100

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Serum response factor (SRF) is a ubiquitously expressed transcription factor that binds to a DNA cis element known as the CArG box, which is found in the proximal regulatory regions of over 200 experimentally validated target genes. Genetic deletion of SRF is incompatible with life in a variety of animals from different phyla. In mice, loss of SRF throughout the early embryo results in gastrulation defects precluding analyses in individual organ systems. Genetic inactivation studies using conditional or inducible promoters directing the expression of the bacteriophage Cre recombinase have shown a vital role for SRF in such cellular processes as contractility, cell migration, synaptic activity, inflammation, and cell survival. A growing number of experimental and human diseases are associated with changes in SRF expression, suggesting that SRF has a role in the pathogenesis of disease. This review summarizes data from experimental model systems and human pathology where SRF expression is either deliberately or naturally altered. Genomic DNA is a quaternary code comprising proteincoding and non-protein-coding sequences. While the protein-coding sequences are well-defined and increasingly understood, we are only beginning to elucidate the hidden information within the vast landscape of the non-proteincoding sequences. The field of comparative genomics has facilitated the identification of transcription factor-binding sites (TFBS) and microRNAs (miRs), which, aside from repetitive DNA sequences, are among the more easily decipherable non-protein-coding sequences in the human genome. Together, TFBS and miRs have essential roles in cell fate determination and cellular homeostasis of most life forms. Sequence variations (eg, single-nucleotide polymorphisms, SNPs) in the TFBS, miRs, and miR target sequences alter gene/protein expression and thus disturb homeostasis leading to disease. 1-4 A major imperative, therefore, is decoding the non-protein-coding genome relating to gene regulation to gain a full understanding of how DNA-binding transcription factors and the estimated one million or more TFBS direct normal biological processes.Serum response factor (SRF) is the founding member of the MADS-box family of transcription factors 5 and is one of the best understood DNA-binding proteins in the human proteome. The DNA-binding properties of SRF and its molecular cloning were first defined in the laboratory of Richard Treisman. 6,7 SRF has relatively low intrinsic transcriptional activity, but its interaction with over 60 cofactors confers strong transactivation potential in a cell-and context-specific manner. At least two major signaling pathways converge upon SRF to direct the programs of gene expression. 8,9 The classic pathway involves growth factor stimulation and mitogen-activated protein kinase signaling leading to the phosphorylation of the SRF cofactor, ELK1, and the activation of growth-related genes. 10,11 The second regulatory pathway occurs through Rho-dependent changes in actin dynamics. 12 In this pathway, si...

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Section: Gastrointestinal Tractmentioning

confidence: 99%

Role of serum response factor in the pathogenesis of disease

Miano

2010

Laboratory Investigation

119

100

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“…1A; see also (Wallace and Burns, 2005;Niessen et al, 2005;Mericskay et al, 2007). We also identified a new cluster composed of genes (i.e.…”

Section: Intermuscular Tendons Are Present In the Vertebrate Stomachmentioning

confidence: 77%

Intermuscular tendons are essential for the development of vertebrate stomach

2009

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Gastrointestinal motility is ensured by the correct coordination of the enteric nervous system and the visceral smooth muscle cells (SMCs), and defective development of SMCs results in gut malformations and intestinal obstructions. In order to identify the molecular mechanisms that control the differentiation of the visceral mesenchyme into SMCs in the vertebrate stomach, we developed microarrays to analyze the gene expression profiles of undifferentiated and differentiated avian stomachs. We identify Scleraxis, a basic-helix-loop-helix transcription factor, as a new marker of stomach mesenchyme and find that expression of Scleraxisdefines the presence of two tendons closely associated to the two visceral smooth muscles. Using targeted gene misexpression, we show that FGF signaling is sufficient to induce Scleraxis expression and to establish two tendon domains adjacent to the smooth muscle structures. We also demonstrate that the tendon organization is perturbed by altering Scleraxisexpression or function. Moreover, using primary cells derived from stomach mesenchyme, we find that undifferentiated stomach mesenchyme can give rise to both SMCs and tendon cells. These data show that upon FGF activation, selected stomach mesenchymal cells are primed to express Scleraxis and to differentiate into tendon cells. Our findings identify a new anatomical and functional domain in the vertebrate stomach that we characterize as being two intermuscular tendons closely associated with the visceral SMC structures. We also demonstrate that the coordinated development of both tendon and smooth muscle domains is essential for the correct morphogenesis of the stomach.

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“…Previous models of myopathy associated with CIPO-like disease have involved inducible deletion of the transcriptional regulator, serum response factor, from smooth muscle, 38,39 or deletion of the smooth muscleerestricted factor smoothelin A. 40 In both cases, the CIPO phenotype was associated with loss of smooth muscle cell contractility rather than active loss of smooth muscle cells; serum response factor deletion failed to affect smooth muscle cell numbers, whereas smoothelin A loss triggered smooth muscle cell hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mutation in Nucleoporin 35 Causes Murine Degenerative Colonic Smooth Muscle Myopathy

Parish

Stamp

Lorenzo

et al. 2016

The American Journal of Pathology

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Chronic intestinal pseudo-obstruction (CIPO) is a rare but life-threatening disease characterized by severe intestinal dysmotility. Histopathologic studies in CIPO patients have identified several different mechanisms that appear to be involved in the dysmotility, including defects in neurons, smooth muscle, or interstitial cells of Cajal. Currently there are few mouse models of the various forms of CIPO. We generated a mouse with a point mutation in the RNA recognition motif of the Nup35 gene, which encodes a component of the nuclear pore complex. Nup35 mutants developed a severe megacolon and exhibited a reduced lifespan. Histopathologic examination revealed a degenerative myopathy that developed after birth and specifically affected smooth muscle in the colon; smooth muscle in the small bowel and the bladder were not affected. Furthermore, no defects were found in enteric neurons or interstitial cells of Cajal. Nup35 mice are likely to be a valuable model for the subtype of CIPO characterized by degenerative myopathy. Our study also raises the possibility that Nup35 polymorphisms could contribute to some cases of CIPO. (Am J Pathol 2016 http://dx

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Inducible Mouse Model of Chronic Intestinal Pseudo-Obstruction by Smooth Muscle-Specific Inactivation of the SRF Gene

Cited by 51 publications

References 30 publications

Role of serum response factor in the pathogenesis of disease

Role of serum response factor in the pathogenesis of disease

Intermuscular tendons are essential for the development of vertebrate stomach

A Novel Mutation in Nucleoporin 35 Causes Murine Degenerative Colonic Smooth Muscle Myopathy

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