Britsch S.. The neuregulin-I/ErbB signaling system in development and disease. Adv Anat Embryol Cell Biol 190: 1-65

Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany.
Advances in anatomy, embryology, and cell biology (Impact Factor: 17). 02/2007; 190:1-65. DOI: 10.1007/978-3-540-37107-6_1
Source: PubMed


Neuregulins (NRGs) comprise a large family of EGF-like signaling molecules involved in cell-cell communication during development and disease. The neuregulin family of ligands has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins. In contrast, the NRG1 proteins have been demonstrated to play important roles during the development of the nervous system, heart, and mammary glands. For example, NRG1 has essential functions in the development of neural crest cells and some of their major derivatives, like Schwann cells and sympathetic neurons. NRG1 controls the trabeculation of the myocardial musculature and the ductal differentiation of the mammary epithelium. Moreover, there is emerging evidence for the involvement of NRG signals in the development and function of several other organ systems, and in human disease, including breast cancer and schizophrenia. Many different isoforms of the Neuregulin-1 gene are synthesized. Such isoforms differ in their tissue-specific expression patterns and their biological activities, thereby contributing to the great diversity of the in vivo functions of NRG1. Neuregulins transmit their signals to target cells by interacting with transmembrane tyrosine kinase receptors of the ErbB family. This family includes four members, the epidermal growth factor receptor (EGF-R, ErbB1, ErbB2, ErbB3, and ErbB4). Receptor-ligand interaction induces the heterodimerization of receptor monomers, which in turn results in the activation of intracellular signaling cascades and the induction of cellular responses including proliferation, migration, differentiation, and survival or apoptosis. In vivo, functional NRG1 receptors are heterodimers composed of ErbB2 with either an ErbB3, or ErbB4 molecule. The tissue-specific distribution of the different receptor types further contributes to the diversity and specificity of the biological functions of this signaling pathway. It is a typical feature of the Neuregulin-1/ErbB signaling pathway to control sequential steps during the development of a particular organ system. For example, this pathway functions in early precursor proliferation, maturation, as well as in the myelination of Schwann cells. The systematic analysis of genetic models that have been established by the help of conventional as well as conditional gene targeting strategies in mice was instrumental for the uncovering of the multitude of biological functions of this signaling system. In this review the basic biology of the Neuregulin-1/ErbB system and how it relates to the in vivo functions were discussed with special emphasis to transgenic techniques in mice.

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    • "The ErbB2 / ErbB3 receptors are expressed in mouse neural crest cells that colonize the gut during development and in adult intestinal epithelia of both humans and mice ( Paratore et al . , 2002 ; Britsch , 2007 ) . However , a detailed characterization of the NRG1 system in the human colonic neuro - musculature system responsible for GI motility is still lacking . "
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    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.
    Full-text · Article · Oct 2015 · Frontiers in Cellular Neuroscience
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    • "Several studies reported that ErbB1 – ErbB4 and their ligands , including EGF , AREG , and NRG activity , are required for airway epithelial cell proliferation and repair ( Britsch , 2007 ; Dammann et al . , 2003 ; Fischer et al . "
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    ABSTRACT: The purpose of this study is to determine the possible changes in the localization of the four Epidermal Growth Factor Receptors and three ligands in quail lungs from the first day of hatching until the 125th after hatching using immunohistochemical methods. Immunohistochemical results demonstrated that four EGFRs and their ligands are chiefly located in the cytoplasm of cells. Additionally, ErbB4, AREG, and NRG1 are localized to the nucleus and nucleolus, but EGF is present in the nucleolus. ErbB2 was also found in the cell membrane. In the epithelium of secondary bronchi, the goblet cells only exhibited ErbB1 and ErbB2, whereas the basal and ciliated cells exhibited EGFRs and ligands immunoreactivity. The atrial granular cells displayed moderate levels of ErbB1-ErbB3 and EGF and strong levels of ErbB4, AREG, and NRG1 immunoreactivity. While the squamous atrial cells and squamous respiratory cells of air capillaries and endothelial cells of blood capillaries exhibited moderate to strong ErbB2, ErbB4, AREG, and NRG1 immunoreactivity, they had negative or weak ErbB1, ErbB3, and EGF immunoreactivity. The expression levels of ErbB2-ErbB4, EGF, AREG, and NRG1 were also detected in fibroblasts. Although ErbB2 was highly expressed in the bronchial and vascular smooth muscle cells, weak expression of ErbB1, ErbB3, AREG and EGF and moderate expression of ErbB4 and NRG1 were observed. Macrophages were only negative for ErbB1. In conclusion, these data indicate that the EGFR-system is functionally active at hatching, which supports the hypothesis that the members of EGFR-system play several cell-specific roles in quail lung growth after hatching. Microsc. Res. Tech., 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Jul 2015 · Microscopy Research and Technique
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    • "The neuregulin1/ErbB system plays an important role in Schwann cell (SC) behavior both in normal and pathological conditions [1] and the possibility to manipulate it gives new perspectives to improve posttraumatic nerve regeneration [2] [3] [4]. The ErbB receptor family consists of four tyrosine kinase receptors: epidermal growth factor receptor (EGFR, also called ErbB1 or HER1), ErbB2, ErbB3, and ErbB4 [5]. "
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    ABSTRACT: The neuregulin1/ErbB system plays an important role in Schwann cell behavior both in normal and pathological conditions. Upon investigation of the expression of the neuregulin1/ErbB system in vitro, we explored the possibility to manipulate the system in order to increase the migration of Schwann cells, that play a fundamental role in the peripheral nerve regeneration. Comparison of primary cells and stable cell lines shows that both primary olfactory bulb ensheathing cells and a corresponding cell line express ErbB1-ErbB2 and neuregulin1, and that both primary Schwann cells and a corresponding cell line express ErbB2-ErbB3, while only primary Schwann cells express neuregulin1. To interfere with the neuregulin1/ErbB system, the soluble extracellular domain of the neuregulin1 receptor ErbB4 (ecto-ErbB4) was expressed in vitro in the neuregulin1 expressing cell line, and an unexpected increase in cell motility was observed. In vitro experiments suggest that the back signaling mediated by the transmembrane neuregulin1 plays a role in the migratory activity induced by ecto-ErbB4. These results indicate that ecto-ErbB4 could be used in vivo as a tool to manipulate the neuregulin1/ErbB system.
    Full-text · Article · Aug 2014 · BioMed Research International
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