Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss

Chen, Suzhen; Río, Carlos; Ji, Ru-Rong; Dikkes, Pieter; Coggeshall, Richard E.; Woolf, Clifford J.; Corfas, Gabriel

doi:10.1038/nn1139

Cited by 155 publications

(158 citation statements)

References 47 publications

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“…The mutant receptors, however, retained their ability to bind to ligands and dimerize with other ErbBs, and therefore could act in a dominant fashion to inhibit the endogenous ErbB signals. DNErbBs have been successfully used in cell culture and mouse studies to block the ErbB pathway (e.g., Ram et al, 2000;Chen et al, 2003); and in our experiments, coexpression of any of the four DN-ErbBs with the wild type ErbB2 efficiently suppressed the mesodermal induction by ErbB2 (Fig. 6A), confirming that DN-ErbBs acted as dominant negative receptors.…”

Section: Blocking Erbb Signals Leads To Axial Defects Associated Withsupporting

confidence: 82%

Regulation of early Xenopus development by ErbB signaling

Nie

Chang

2005

Developmental Dynamics

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ErbB signaling has long been implicated in cancer formation and progression and is shown to regulate cell division, migration, and death during tumorigenesis. The functions of the ErbB pathway during early vertebrate embryogenesis, however, are not well understood. Here we report characterization of ErbB activities during early frog development. Gain-of-function analyses show that EGFR, ErbB2, and ErbB4 induce ectopic tumor-like cell mass that contains increased numbers of mitotic cells. Both the muscle and the neural markers are expressed in these ectopic protrusions. ErbBs also induce mesodermal markers in ectodermal explants. Loss-of-function studies using carboxyl terminal-truncated dominant-negative ErbB receptors demonstrate that blocking ErbB signals leads to defective gastrulation movements and malformation of the embryonic axis with a reduction in the head structures in early frog embryos. These data, together with the observation that ErbBs are expressed early during frog embryogenesis, suggest that ErbBs regulate cell proliferation, movements, and embryonic patterning during early Xenopus development. Developmental Dynamics 235:301-314, 2006.

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Section: Blocking Erbb Signals Leads To Axial Defects Associated Withsupporting

confidence: 82%

Regulation of early Xenopus development by ErbB signaling

Nie

Chang

2005

Developmental Dynamics

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“…In addition to large (Ն1 m), myelinated axons, there are small axons, such as C fibers that conduct nociceptive signal and are ensheathed by nonmyelinating SCs (6,14). We investigated whether Erbin is necessary for ensheathment of unmyelinated axons.…”

Section: Resultsmentioning

confidence: 99%

“…This notion is supported by mouse genetic studies that mutation of NRG1, ErbB2, or ErbB3 genes causes severe deficits of peripheral neurons and SCs (3,4,(10)(11)(12)(13). Disruption of NRG1/ErbB signaling by a dominant negative approach led to deficits in myelinating and nonmyelinating SCs (14,15). Intracellularly, NRG1 stimulates various cascades including the PI3K/Akt pathway that have been implicated in myelinaton (16).…”

mentioning

confidence: 94%

Erbin regulates NRG1 signaling and myelination

Tao

Dai

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Neuregulin 1 (NRG1) plays a critical role in myelination. However, little is known about regulatory mechanisms of NRG1 signaling. We show here that Erbin, a protein that contains leucine-rich repeats (LRR) and a PSD95-Dlg-Zol (PDZ) domain and that interacts specifically with ErbB2, is necessary for NRG1 signaling and myelination of peripheral nervous system (PNS). In Erbin null mice, myelinated axons were hypomyelinated with reduced expression of P0, a marker of mature myelinating Schwann cells (SCs), whereas unmyelinated axons were aberrantly ensheathed in Remak bundles, with increased numbers of axons in the bundles and in pockets. The morphological deficits were associated with decreased nerve conduction velocity and increased sensory threshold to mechanistic stimulation. These phenotypes were duplicated in erbin ⌬C/⌬C mice, in which Erbin lost the PDZ domain to interact with ErbB2. Moreover, ErbB2 was reduced at protein levels in both Erbin mutant sciatic nerves, and ErbB2 became unstable and NRG1 signaling compromised when Erbin expression was suppressed. These observations indicate a critical role of Erbin in myelination and identify a regulatory mechanism of NRG1 signaling. Our results suggest that Erbin, via the PDZ domain, binds to and stabilizes ErbB2, which is necessary for NRG1 signaling that has been implicated in tumorigenesis, heart development, and neural function.ErbB2 ͉ PDZ ͉ protein stability ͉ Schwann cells ͉ Akt M yelin sheath wraps axons to ensure the velocity and timing of action potential propagation and insulates neuronal activity. Impaired myelin formation and maintenance have been implicated in various neurological and psychiatric disorders including schizophrenia, multiple sclerosis, and Charcot-Marie-Tooth neuropathy disease (1, 2). Myelination is a tightly controlled, complex process. In the peripheral nervous system (PNS), neuregulin 1 (NRG1) has emerged as a key axon-derived factor that regulates myelination. Disruption of NRG1 signaling by ablating either the EGF domain that is contained in all isoforms or type III isoform leads to an almost complete loss of SCs and of the sensory and motor neurons that they support (3, 4). Recent studies have suggested that the level of NRG1 in the axon is critical for myelination (5, 6).NRG1 acts by stimulating a family of single transmembrane receptor tyrosine kinases called ErbB proteins (1). Although NRG1 was isolated as a ''ligand'' to activate ErbB2, it does not interact with the receptor (7). However, ErbB3 can bind NRG1 but its homodimers are catalytically inactive, indicating impaired kinase function (8). Therefore, ErbB2 and ErbB3, major ErbB proteins in SCs, need to form heterodimers with each other to be functional (9). This notion is supported by mouse genetic studies that mutation of NRG1, ErbB2, or ErbB3 genes causes severe deficits of peripheral neurons and SCs (3, 4, 10-13). Disruption of NRG1/ErbB signaling by a dominant negative approach led to deficits in myelinating and nonmyelinating SCs (14,15). Intracellularly, NRG1 stimu...

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“…Sensory innervation only occurs in dentinal tubules with viable odontoblasts that maintain their columnar form. This relationship, critical for odontoblast behaviour, could be similar to the role that neuregulin and its ErbB receptors play in the control of cell morphology and in hyperalgesia [42]. Much is still unknown, including which proteins mediate signals between the odontoblasts and nerves and whether cilium acts as a signal integrator.…”

Section: Pain Mechanismsmentioning

confidence: 99%

“…This highlights that the terminal web is a pivotal zone of the pulp/dentin complex for sensing external stimuli. External stimuli causing dentinal fluid movements and or odontoblasts and/or nerve complex responses may represent a unique mechanosensory system with odontoblasts acting as sensor cells in the pain of dentin hypersensitivity [42]. …”

Section: Pain Mechanismsmentioning

confidence: 99%

Dentin hypersensitivity: pain mechanisms and aetiology of exposed cervical dentin

et al. 2012

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ObjectivesThe paper’s aim is to review dentin hypersensitivity (DHS), discussing pain mechanisms and aetiology.Materials and methodsLiterature was reviewed using search engines with MESH terms, DH pain mechanisms and aetiology (including abrasion, erosion and periodontal disease).ResultsThe many hypotheses proposed for DHS attest to our lack of knowledge in understanding neurophysiologic mechanisms, the most widely accepted being the hydrodynamic theory. Dentin tubules must be patent from the oral environment to the pulp. Dentin exposure, usually at the cervical margin, is due to a variety of processes involving gingival recession or loss of enamel, predisposing factors being periodontal disease and treatment, limited alveolar bone, thin biotype, erosion and abrasion.ConclusionsThe current pain mechanism of DHS is thought to be the hydrodynamic theory. The initiation and progression of DHS are influenced by characteristics of the teeth and periodontium as well as the oral environment and external influences. Risk factors are numerous often acting synergistically and always influenced by individual susceptibility.Clinical relevanceWhilst the pain mechanism of DHS is not well understood, clinicians need to be mindful of the aetiology and risk factors in order to manage patients’ pain and expectations and prevent further dentin exposure with subsequent sensitivity.

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Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss

Cited by 155 publications

References 47 publications

Regulation of early Xenopus development by ErbB signaling

Regulation of early Xenopus development by ErbB signaling

Erbin regulates NRG1 signaling and myelination

Dentin hypersensitivity: pain mechanisms and aetiology of exposed cervical dentin

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