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Expression and function of Neuregulin 1 and its signaling system ERBB2/3 in the enteric nervous system.

Barrenschee M, Lange C, Cossais F, Egberts JH, Becker T, Wedel T, Böttner M - Front Cell Neurosci (2015)

Bottom Line: NRG1 significantly enhanced growth parameters in enteric nerve cell cultures and ErB3 mRNA expression was down-regulated upon NRG1 stimulation.The down-regulation of ErbB3/ErbB2 in GDNF stimulated nerve cell cultures points to an interaction of both neurotrophic factors.Thus, the data may provide a basis to assess disturbed signaling components of the NRG1 system in enteric neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Neurogastroenterology, Institute of Anatomy, Christian-Albrechts-University of Kiel Kiel, Germany.

ABSTRACT
Neuregulin 1 (NRG1) is suggested to promote the survival and maintenance of the enteric nervous system (ENS). As deficiency in its corresponding receptor signaling complex ERBB2/ERBB3 leads to postnatal colonic hypo/aganglionosis we assessed the distributional and expressional pattern of the NRG1-ERBB2/ERBB3 system in the human colon and explored the neurotrophic capacity of NRG1 on cultured enteric neurons. Site-specific mRNA expression of the NRG1-ERBB2/3 system was determined in microdissected samples harvested from enteric musculature and ganglia. Localization of NRG1, ERBB2 and ERBB3 was determined by dual-label-immunohistochemistry using pan-neuronal and pan-glial markers. Morphometric analysis was performed on NRG1-stimulated rat enteric nerve cultures to evaluate neurotrophic effects. mRNA expression of the NRG1-ERBB2/3 system was determined by qPCR. Co-localization of NRG1 with neuronal or synaptic markers was analyzed in enteric nerve cultures stimulated with glial cell line-derived neurotrophic factor (GDNF). The NRG1 system was expressed in both neurons and glial cells of enteric ganglia and in nerve fibers. NRG1 significantly enhanced growth parameters in enteric nerve cell cultures and ErB3 mRNA expression was down-regulated upon NRG1 stimulation. GDNF negatively regulates ErbB2 and ErbB3 mRNA expression. The NRG1-ERBB2/3 system is physiologically present in the human ENS and NRG1 acts as a neurotrophic factor for the ENS. The down-regulation of ErbB3/ErbB2 in GDNF stimulated nerve cell cultures points to an interaction of both neurotrophic factors. Thus, the data may provide a basis to assess disturbed signaling components of the NRG1 system in enteric neuropathies.

No MeSH data available.


Related in: MedlinePlus

Localization of NRG1, ERBB2 and ERBB3 in the colonic myenteric plexus and circular musculature of the adult human colon. NRG1 immunopositive signals were identified in myenteric ganglia with robust staining in neuronal somata and weaker signals in the surrounding neuropil (A). Perinuclear staining (arrowhead) was detected on all glial nuclei (A). In the circular musculature, smooth NRG1 immunoreactivity was observed as faint signals with homogenous distribution (B). ERBB2 immunoreactivity in myenteric ganglia (C) appeared to be less pronounced compared to the surrounding neuropil but showed additional strong granular staining (arrowheads) confined to cell somata. In the circular musculature, ERBB2 immunoreactivity (D) displayed slight signals similar to NRG1 and also with uniform distribution. ERBB3 immunoreactivity was also found in myenteric ganglia (E) accumulated in neuronal somata of singe neurons and also observed area-wide throughout the ganglia as well as in nerve fibers running within the CM layer (F). Blue color: haematoxylin counterstain. Bars: 20 μm.
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Figure 2: Localization of NRG1, ERBB2 and ERBB3 in the colonic myenteric plexus and circular musculature of the adult human colon. NRG1 immunopositive signals were identified in myenteric ganglia with robust staining in neuronal somata and weaker signals in the surrounding neuropil (A). Perinuclear staining (arrowhead) was detected on all glial nuclei (A). In the circular musculature, smooth NRG1 immunoreactivity was observed as faint signals with homogenous distribution (B). ERBB2 immunoreactivity in myenteric ganglia (C) appeared to be less pronounced compared to the surrounding neuropil but showed additional strong granular staining (arrowheads) confined to cell somata. In the circular musculature, ERBB2 immunoreactivity (D) displayed slight signals similar to NRG1 and also with uniform distribution. ERBB3 immunoreactivity was also found in myenteric ganglia (E) accumulated in neuronal somata of singe neurons and also observed area-wide throughout the ganglia as well as in nerve fibers running within the CM layer (F). Blue color: haematoxylin counterstain. Bars: 20 μm.

Mentions: Branching points and ganglion-like aggregates were counted in three randomly assigned optical fields and the mean value was calculated. Data were presented as mean branching points per optical field and mean number of ganglion-like aggregates per optical field. Ganglion-like aggregates are defined as a cluster of neurons creating assemblage points, resembling enteric ganglia (Figure 7). Experiments were carried out in nine replicates (2 and 20 ng/ml NRG1 vs. control).


Expression and function of Neuregulin 1 and its signaling system ERBB2/3 in the enteric nervous system.

Barrenschee M, Lange C, Cossais F, Egberts JH, Becker T, Wedel T, Böttner M - Front Cell Neurosci (2015)

Localization of NRG1, ERBB2 and ERBB3 in the colonic myenteric plexus and circular musculature of the adult human colon. NRG1 immunopositive signals were identified in myenteric ganglia with robust staining in neuronal somata and weaker signals in the surrounding neuropil (A). Perinuclear staining (arrowhead) was detected on all glial nuclei (A). In the circular musculature, smooth NRG1 immunoreactivity was observed as faint signals with homogenous distribution (B). ERBB2 immunoreactivity in myenteric ganglia (C) appeared to be less pronounced compared to the surrounding neuropil but showed additional strong granular staining (arrowheads) confined to cell somata. In the circular musculature, ERBB2 immunoreactivity (D) displayed slight signals similar to NRG1 and also with uniform distribution. ERBB3 immunoreactivity was also found in myenteric ganglia (E) accumulated in neuronal somata of singe neurons and also observed area-wide throughout the ganglia as well as in nerve fibers running within the CM layer (F). Blue color: haematoxylin counterstain. Bars: 20 μm.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4585281&req=5

Figure 2: Localization of NRG1, ERBB2 and ERBB3 in the colonic myenteric plexus and circular musculature of the adult human colon. NRG1 immunopositive signals were identified in myenteric ganglia with robust staining in neuronal somata and weaker signals in the surrounding neuropil (A). Perinuclear staining (arrowhead) was detected on all glial nuclei (A). In the circular musculature, smooth NRG1 immunoreactivity was observed as faint signals with homogenous distribution (B). ERBB2 immunoreactivity in myenteric ganglia (C) appeared to be less pronounced compared to the surrounding neuropil but showed additional strong granular staining (arrowheads) confined to cell somata. In the circular musculature, ERBB2 immunoreactivity (D) displayed slight signals similar to NRG1 and also with uniform distribution. ERBB3 immunoreactivity was also found in myenteric ganglia (E) accumulated in neuronal somata of singe neurons and also observed area-wide throughout the ganglia as well as in nerve fibers running within the CM layer (F). Blue color: haematoxylin counterstain. Bars: 20 μm.
Mentions: Branching points and ganglion-like aggregates were counted in three randomly assigned optical fields and the mean value was calculated. Data were presented as mean branching points per optical field and mean number of ganglion-like aggregates per optical field. Ganglion-like aggregates are defined as a cluster of neurons creating assemblage points, resembling enteric ganglia (Figure 7). Experiments were carried out in nine replicates (2 and 20 ng/ml NRG1 vs. control).

Bottom Line: NRG1 significantly enhanced growth parameters in enteric nerve cell cultures and ErB3 mRNA expression was down-regulated upon NRG1 stimulation.The down-regulation of ErbB3/ErbB2 in GDNF stimulated nerve cell cultures points to an interaction of both neurotrophic factors.Thus, the data may provide a basis to assess disturbed signaling components of the NRG1 system in enteric neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Neurogastroenterology, Institute of Anatomy, Christian-Albrechts-University of Kiel Kiel, Germany.

ABSTRACT
Neuregulin 1 (NRG1) is suggested to promote the survival and maintenance of the enteric nervous system (ENS). As deficiency in its corresponding receptor signaling complex ERBB2/ERBB3 leads to postnatal colonic hypo/aganglionosis we assessed the distributional and expressional pattern of the NRG1-ERBB2/ERBB3 system in the human colon and explored the neurotrophic capacity of NRG1 on cultured enteric neurons. Site-specific mRNA expression of the NRG1-ERBB2/3 system was determined in microdissected samples harvested from enteric musculature and ganglia. Localization of NRG1, ERBB2 and ERBB3 was determined by dual-label-immunohistochemistry using pan-neuronal and pan-glial markers. Morphometric analysis was performed on NRG1-stimulated rat enteric nerve cultures to evaluate neurotrophic effects. mRNA expression of the NRG1-ERBB2/3 system was determined by qPCR. Co-localization of NRG1 with neuronal or synaptic markers was analyzed in enteric nerve cultures stimulated with glial cell line-derived neurotrophic factor (GDNF). The NRG1 system was expressed in both neurons and glial cells of enteric ganglia and in nerve fibers. NRG1 significantly enhanced growth parameters in enteric nerve cell cultures and ErB3 mRNA expression was down-regulated upon NRG1 stimulation. GDNF negatively regulates ErbB2 and ErbB3 mRNA expression. The NRG1-ERBB2/3 system is physiologically present in the human ENS and NRG1 acts as a neurotrophic factor for the ENS. The down-regulation of ErbB3/ErbB2 in GDNF stimulated nerve cell cultures points to an interaction of both neurotrophic factors. Thus, the data may provide a basis to assess disturbed signaling components of the NRG1 system in enteric neuropathies.

No MeSH data available.


Related in: MedlinePlus