No neuronal loss, but alterations of the GDNF system in asymptomatic diverticulosis

Barrenschee, Martina; Wedel, Thilo; Lange, Christina; Hohmeier, Ines; Cossais, François; Ebsen, Michael; Vogel, Ilka; Böttner, Martina

doi:10.1371/journal.pone.0171416

Cited by 24 publications

(29 citation statements)

References 33 publications

(48 reference statements)

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“…investigated by Böttner et al (2013), who observed decreased gene expression levels of the receptors for GDNF, RET, and GFRα1. A refined analysis revealed that the down-regulation of both receptors was most pronounced in myenteric ganglia (Barrenschee et al, 2017), thereby resembling the actual data on the NRG1-ErbB2/ErbB3 system in DD: The ErbB3 receptor predominantly expressed in enteric neuronal tissue is diminished in DD, whereas the ErbB2 receptor primarily expressed by enteric smooth muscle cells (Barrenschee et al, 2015) is not affected.…”

Section: Neurotrophic Factors and Their Corresponding Receptors In Ddsupporting

confidence: 66%

“…Image acquisition, processing, and analysis were performed as previously described (Barrenschee et al, 2017). Briefly, fluorescence immunohistochemical signals of myenteric ganglia (n = 8) were recorded in specimens of controls and patients with DD.…”

Section: Quantitation Of Immunofluorescence Signalsmentioning

confidence: 99%

“…enteric neuropathy (Simpson et al, 2009) characterized by remodeling of nerve tissue (Golder et al, 2003), impaired intestinal motility patterns (Gallego et al, 2013), disturbed enteric neurotransmission (Espin et al, 2014), and a relative loss of enteric nerve cells (Iwase et al, 2005;Deduchovas et al, 2008;Wedel et al, 2010). It has been shown that GDNF, a potent growth factor for the ENS, is impaired not only in DD (Böttner et al, 2013), but also in asymptomatic diverticulosis suggesting that a deficient GDNF system may trigger the enteric nerve cell decrease in DD (Barrenschee et al, 2017).…”

Section: Neurotrophic Factors and Their Corresponding Receptors In Ddmentioning

confidence: 99%

“…Moreover, the underlying cellular and molecular mechanisms leading to DD are largely unknown (Simpson and Spiller, 2002). However, since DD is associated with a lack of glial-cell line derived neurotrophic factor (GDNF) and its corresponding receptors (Böttner et al, 2013), a general involvement of neurotrophic factors may play a role in the pathogenesis of DD, e.g., a deficient GDNF system could be a primary trigger for the reduced neuronal number shown in DD (Barrenschee et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Impaired Expression of Neuregulin 1 and Nicotinic Acetylcholine Receptor β4 Subunit in Diverticular Disease

Barrenschee

Cossais

Böttner

et al. 2019

Front. Cell. Neurosci.

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Neuregulin 1 (NRG1) regulates the expression of the nicotinic acetylcholine receptor (nAChR) and is suggested to promote the survival and maintenance of the enteric nervous system (ENS), since deficiency of its corresponding receptor complex ErbB2/ErbB3 leads to postnatal colonic aganglionosis. As diverticular disease (DD) is associated with intestinal hypoganglionosis, the NRG1-ErbB2/ErbB3 system and the nAChR were studied in patients with DD and controls. Samples of tunica muscularis of the sigmoid colon from patients with DD (n = 8) and controls (n = 11) were assessed for mRNA expression of NRG1, ErbB2, and ErbB3 and the nAChR subunits α3, α5, α7, β2, and β4. Site-specific gene expression levels of the NRG1-ErbB2/3 system were determined in myenteric ganglia harvested by laser microdissection (LMD). Localization studies were performed by immunohistochemistry for the NRG1-ErbB2/3 system and nAChR subunit β4. Rat enteric nerve cell cultures were stimulated with NRG1 or glial-cell line derived neurotrophic factor (GDNF) for 6 days and mRNA expression of the aforementioned nAchR was measured. NRG1, ErbB3, and nAChR subunit β4 expression was significantly down-regulated in both the tunica muscularis and myenteric ganglia of patients with DD compared to controls, whereas mRNA expression of ErbB3 and nAChR subunits β2, α3, α5, and α7 remained unaltered. NRG1, ErbB3, and nAChR subunit β4 immunoreactive signals were reduced in neuronal somata and the neuropil of myenteric ganglia from patients with DD compared to control. nAChR subunit β4 exhibited also weaker immunoreactive signals in the tunica muscularis of patients with DD. NRG1 treatment but not GDNF treatment of enteric nerve cell cultures significantly enhanced mRNA expression of nAchR β4. The down-regulation of NRG1 and ErbB3 in myenteric ganglia of patients with DD supports the hypothesis that intestinal hypoganglionosis observed in DD may be attributed to a lack of neurotrophic factors. Regulation of nAChR subunit β4 by NRG1 and decreased nAChR β4 in patients with DD provide evidence that a lack of NRG1 may affect the composition of enteric neurotransmitter receptor subunits thus contributing to the intestinal motility disorders previously reported in DD.

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Section: Neurotrophic Factors and Their Corresponding Receptors In Ddsupporting

confidence: 66%

Section: Quantitation Of Immunofluorescence Signalsmentioning

confidence: 99%

Section: Neurotrophic Factors and Their Corresponding Receptors In Ddmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impaired Expression of Neuregulin 1 and Nicotinic Acetylcholine Receptor β4 Subunit in Diverticular Disease

Barrenschee

Cossais

Böttner

et al. 2019

Front. Cell. Neurosci.

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“…Mutations in glial cell line-derived neurotrophic factor ( GDNF ) have been suggested to act in concert with RET mutations to produce aganglionic megacolon (Hirschsprung’s disease), which is characterised by congenital absence of intrinsic ganglion cells in the myenteric and submucosal plexuses of the GI tract 30. Impaired GDNF function has been shown at gene and protein level to occur in diverticular disease and during early stages of diverticula formation 31. Plausible links to neuronal physiology are also evident for GPR158 , a G-protein coupled orphan receptor32 and brain-derived neurotropic factor.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Schafmayer¹,

Harrison²,

Buch³

et al. 2019

Gut

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ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

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Changes in Colonic Structure and Mucosal Inflammation

Crafa

Díaz‐Cano

2022

Colonic Diverticular Disease

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No neuronal loss, but alterations of the GDNF system in asymptomatic diverticulosis

Cited by 24 publications

References 33 publications

Impaired Expression of Neuregulin 1 and Nicotinic Acetylcholine Receptor β4 Subunit in Diverticular Disease

Impaired Expression of Neuregulin 1 and Nicotinic Acetylcholine Receptor β4 Subunit in Diverticular Disease

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Changes in Colonic Structure and Mucosal Inflammation

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