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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

mRNA expression of NRG1, ERBB2 and ERBB3 in enteric nerve cell cultures in response to NRG1 or GDNF treatment. NRG1 mRNA expression in enteric nerve cells were not regulated by NRG1 or GDNF stimulation (A), whereas NRG1 decreased mRNA levels of ERBB3 (C) and GDNF decreased mRNA levels of both ERBB2 and ERBB3 (B,C). Enteric nerve cells were cultured for 6 days. Expression levels of the target gene were normalized to expression of the house-keeping gene HPRT. Data are shown as mean ± SEM, n = 15–18 per experimental group, *p < 0.05, **p < 0.01 vs. control.
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Figure 8: mRNA expression of NRG1, ERBB2 and ERBB3 in enteric nerve cell cultures in response to NRG1 or GDNF treatment. NRG1 mRNA expression in enteric nerve cells were not regulated by NRG1 or GDNF stimulation (A), whereas NRG1 decreased mRNA levels of ERBB3 (C) and GDNF decreased mRNA levels of both ERBB2 and ERBB3 (B,C). Enteric nerve cells were cultured for 6 days. Expression levels of the target gene were normalized to expression of the house-keeping gene HPRT. Data are shown as mean ± SEM, n = 15–18 per experimental group, *p < 0.05, **p < 0.01 vs. control.

Mentions: To investigate the effect of NRG1 and the well-known enteric neurotrophic factor GDNF on gene regulation of the enteric NRG1 system itself, mRNA expression of Nrg1, ErbB2 and ErbB3 were measured by RT-qPCR in rat enteric nerve cell cultures treated with increasing concentrations of NRG1 of 2 ng/ml and 20 ng/ml and 50 ng/ml GDNF for 1 week (Figure 8). Neither NRG1 nor GDNF treatment regulated the Nrg1 mRNA enteric nerve cultures (Figure 8A) and also no regulation of ErbB2 was observed upon NRG1 treatment (Figure 8B). However, 50 ng/ml GDNF administration significantly down-regulated ErbB2 up to 50% as compared to untreated controls (Figure 8B), and the expression of ErbB3 mRNA was down-regulated up to 50% upon both 2 ng/ml NRG1 and 50 ng/ml GDNF (Figure 8C), while 20 ng/ml NRG1 treatment had no significant effect (Figure 8C).


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)

mRNA expression of NRG1, ERBB2 and ERBB3 in enteric nerve cell cultures in response to NRG1 or GDNF treatment. NRG1 mRNA expression in enteric nerve cells were not regulated by NRG1 or GDNF stimulation (A), whereas NRG1 decreased mRNA levels of ERBB3 (C) and GDNF decreased mRNA levels of both ERBB2 and ERBB3 (B,C). Enteric nerve cells were cultured for 6 days. Expression levels of the target gene were normalized to expression of the house-keeping gene HPRT. Data are shown as mean ± SEM, n = 15–18 per experimental group, *p < 0.05, **p < 0.01 vs. control.
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Related In: Results  -  Collection

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Figure 8: mRNA expression of NRG1, ERBB2 and ERBB3 in enteric nerve cell cultures in response to NRG1 or GDNF treatment. NRG1 mRNA expression in enteric nerve cells were not regulated by NRG1 or GDNF stimulation (A), whereas NRG1 decreased mRNA levels of ERBB3 (C) and GDNF decreased mRNA levels of both ERBB2 and ERBB3 (B,C). Enteric nerve cells were cultured for 6 days. Expression levels of the target gene were normalized to expression of the house-keeping gene HPRT. Data are shown as mean ± SEM, n = 15–18 per experimental group, *p < 0.05, **p < 0.01 vs. control.
Mentions: To investigate the effect of NRG1 and the well-known enteric neurotrophic factor GDNF on gene regulation of the enteric NRG1 system itself, mRNA expression of Nrg1, ErbB2 and ErbB3 were measured by RT-qPCR in rat enteric nerve cell cultures treated with increasing concentrations of NRG1 of 2 ng/ml and 20 ng/ml and 50 ng/ml GDNF for 1 week (Figure 8). Neither NRG1 nor GDNF treatment regulated the Nrg1 mRNA enteric nerve cultures (Figure 8A) and also no regulation of ErbB2 was observed upon NRG1 treatment (Figure 8B). However, 50 ng/ml GDNF administration significantly down-regulated ErbB2 up to 50% as compared to untreated controls (Figure 8B), and the expression of ErbB3 mRNA was down-regulated up to 50% upon both 2 ng/ml NRG1 and 50 ng/ml GDNF (Figure 8C), while 20 ng/ml NRG1 treatment had no significant effect (Figure 8C).

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