The Role of ErbB2 Signaling in the Onset of Terminal Differentiation of Oligodendrocytes<i>In Vivo</i>

Kim, Ju Young; Sun, Qiang; Oglesbee, Michael; Yoon, Sung Ok

doi:10.1523/jneurosci.23-13-05561.2003

Cited by 81 publications

(71 citation statements)

References 61 publications

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“…This allowed us to conclude that the cessation of OPC cell division and subsequent terminal OL differentiation is actually a complex, multistep process, which requires several days to reach completion. It has been widely demonstrated that external stimuli from axons and other sources can affect OL survival, differentiation, and myelin sheath formation (Barres et al, 1993(Barres et al, , 1994Barres and Raff, 1999;Stevens et al, 2002;Kim et al, 2003), but to our surprise we found little evidence for an axonal role in controlling OL gene expression. To determine how closely our in vitro study recapitulates normal OL differentiation, we have compared the gene expression profile of our in vitro-generated OLs to that of acutely isolated OLs that have matured in vivo.…”

Section: Ol Differentiation Progresses Fully In the Absence Of Heterocontrasting

confidence: 62%

“…Another interesting finding is the detection of neuroglycan C gene expression, which has been recently characterized as a novel ErbB3/ErbB2 ligand (Kinugasa et al, 2004). This is interesting, because ErbB2 activation enhances OL differentiation and survival (Fernandez et al, 2000;Park et al, 2001;Kim et al, 2003), suggesting the possibility that, in the early stages of OL differentiation, OPC-derived neuroglycan C could provide support for newly forming OLs until they tightly wrap axons, whereupon the axonally expressed ErbB2 ligand neuregulin could then support myelinating OLs (Barres and Raff, 1999).…”

Section: Analysis Of the Genes Most Highly Expressed By Opcsmentioning

confidence: 99%

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Functional Genomic Analysis of Oligodendrocyte Differentiation

Dugas¹,

Tai²,

Speed³

et al. 2006

J. Neurosci.

294

353

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To better understand the molecular mechanisms governing oligodendrocyte (OL) differentiation, we have used gene profiling to quantitatively analyze gene expression in synchronously differentiating OLs generated from pure oligodendrocyte precursor cells in vitro. By comparing gene expression in these OLs to OLs generated in vivo, we discovered that the program of OL differentiation can progress normally in the absence of heterologous cell-cell interactions. In addition, we found that OL differentiation was unexpectedly prolonged and occurred in at least two sequential stages, each characterized by changes in distinct complements of transcription factors and myelin proteins. By disrupting the normal dynamic expression patterns of transcription factors regulated during OL differentiation, we demonstrated that these sequential stages of gene expression can be independently controlled. We also uncovered several genes previously uncharacterized in OLs that encode transmembrane, secreted, and cytoskeletal proteins that are as highly upregulated as myelin genes during OL differentiation. Last, by comparing genomic loci associated with inherited increased risk of multiple sclerosis (MS) to genes regulated during OL differentiation, we identified several new positional candidate genes that may contribute to MS susceptibility. These findings reveal a previously unexpected complexity to OL differentiation and suggest that an intrinsic program governs successive phases of OL differentiation as these cells extend and align their processes, ensheathe, and ultimately myelinate axons.

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Section: Ol Differentiation Progresses Fully In the Absence Of Heterocontrasting

confidence: 62%

Section: Analysis Of the Genes Most Highly Expressed By Opcsmentioning

confidence: 99%

Functional Genomic Analysis of Oligodendrocyte Differentiation

Dugas¹,

Tai²,

Speed³

et al. 2006

J. Neurosci.

294

353

View full text Add to dashboard Cite

show abstract

“…Disruption of NRG1 signaling by DN-ErbB4 or kinase dead ErbB1 impairs oligodendrocyte differentiation in transgenic mice (32,33). However, myelination deficits in the central nervous system (CNS) are relatively minor and limited to frontal brain regions in hypomorphic mutants of type III NRG1 (34).…”

Section: Discussionmentioning

confidence: 99%

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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“…The mechanisms of action of trastuzumab are complex and not fully understood. Described mechanisms include receptor downregulation (Sliwkowski et al, 1999;Ozcelik et al, 2002;Diermeier et al, 2005;Yuste et al, 2005), cell cycle arrest (Kim et al, 2003), inhibition of angiogenesis (Izumi et al, 2002) and induction of antibody-dependent cell-mediated cytotoxicity (ADCC) (Clynes et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

et al. 2008

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Lapatinib is a human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially nonoverlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo-(HER2/HER2) and hetero-(HER2/EGFR and HER2/HER3) dimers. Lapatinibinduced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo, where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.

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The Role of ErbB2 Signaling in the Onset of Terminal Differentiation of OligodendrocytesIn Vivo

Cited by 81 publications

References 61 publications

Functional Genomic Analysis of Oligodendrocyte Differentiation

Functional Genomic Analysis of Oligodendrocyte Differentiation

Erbin regulates NRG1 signaling and myelination

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

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