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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

Co-localization of ERBB3 and PGP 9.5 or S100b in the human colon. ERBB3 (green) was localized in enteric nerve cells visualized by the pan-neuronal marker PGP 9.5 (red, B,E,H) of submucosal (A,C) and myenteric ganglia (D,F), in nerve fibers running within the circular musculature (G,I) as well as in myenteric ganglia visualized with the pan-glial marker S100b (red, J,K). ERBB3 immunoreactive signals were accumulated in somata of single neurons and glial cells and also observed area-wide throughout the ganglia (C,F,L). In the circular musculature (G–I) most ERBB3 immunoreactive signals were restricted to nerve fibers (I, arrowhead). Co-localization (yellow) of NRG1 and PGP 9.5 is shown in merged figures (C,F,I). Co-localization (yellow) of NRG1 and S100b is shown in merged figures (L). Blue color: DAPI staining of nuclei. Bars (A–F): 20 μm; (D–F, G–I): 50 μm, (J–L): 20 μm.
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Figure 5: Co-localization of ERBB3 and PGP 9.5 or S100b in the human colon. ERBB3 (green) was localized in enteric nerve cells visualized by the pan-neuronal marker PGP 9.5 (red, B,E,H) of submucosal (A,C) and myenteric ganglia (D,F), in nerve fibers running within the circular musculature (G,I) as well as in myenteric ganglia visualized with the pan-glial marker S100b (red, J,K). ERBB3 immunoreactive signals were accumulated in somata of single neurons and glial cells and also observed area-wide throughout the ganglia (C,F,L). In the circular musculature (G–I) most ERBB3 immunoreactive signals were restricted to nerve fibers (I, arrowhead). Co-localization (yellow) of NRG1 and PGP 9.5 is shown in merged figures (C,F,I). Co-localization (yellow) of NRG1 and S100b is shown in merged figures (L). Blue color: DAPI staining of nuclei. Bars (A–F): 20 μm; (D–F, G–I): 50 μm, (J–L): 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)

Co-localization of ERBB3 and PGP 9.5 or S100b in the human colon. ERBB3 (green) was localized in enteric nerve cells visualized by the pan-neuronal marker PGP 9.5 (red, B,E,H) of submucosal (A,C) and myenteric ganglia (D,F), in nerve fibers running within the circular musculature (G,I) as well as in myenteric ganglia visualized with the pan-glial marker S100b (red, J,K). ERBB3 immunoreactive signals were accumulated in somata of single neurons and glial cells and also observed area-wide throughout the ganglia (C,F,L). In the circular musculature (G–I) most ERBB3 immunoreactive signals were restricted to nerve fibers (I, arrowhead). Co-localization (yellow) of NRG1 and PGP 9.5 is shown in merged figures (C,F,I). Co-localization (yellow) of NRG1 and S100b is shown in merged figures (L). Blue color: DAPI staining of nuclei. Bars (A–F): 20 μm; (D–F, G–I): 50 μm, (J–L): 20 μm.
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Figure 5: Co-localization of ERBB3 and PGP 9.5 or S100b in the human colon. ERBB3 (green) was localized in enteric nerve cells visualized by the pan-neuronal marker PGP 9.5 (red, B,E,H) of submucosal (A,C) and myenteric ganglia (D,F), in nerve fibers running within the circular musculature (G,I) as well as in myenteric ganglia visualized with the pan-glial marker S100b (red, J,K). ERBB3 immunoreactive signals were accumulated in somata of single neurons and glial cells and also observed area-wide throughout the ganglia (C,F,L). In the circular musculature (G–I) most ERBB3 immunoreactive signals were restricted to nerve fibers (I, arrowhead). Co-localization (yellow) of NRG1 and PGP 9.5 is shown in merged figures (C,F,I). Co-localization (yellow) of NRG1 and S100b is shown in merged figures (L). Blue color: DAPI staining of nuclei. Bars (A–F): 20 μm; (D–F, G–I): 50 μm, (J–L): 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