Defective neuromuscular synaptogenesis in mice expressing constitutively active ErbB2 in skeletal muscle fibers

Ponomareva, Olga N.; Ma, Hualong; Vock, Vita M.; Ellerton, Elaine L.; Moody, Susan E.; Dakour, Ramzi; Chodosh, Lewis A.; Rimer, Mendell

doi:10.1016/j.mcn.2005.10.004

Cited by 23 publications

(34 citation statements)

References 52 publications

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“…It is therefore not clear which cellular target explains the consequences of neuregulin application. Indeed, recent experiments by Ponomareva et al (2006) suggest that critical aspects of the disruption of NMJs in these experiments are explained by the action of neuregulin directly on muscle fibers. To test which effects might be attributable to neuregulin action directly on SCs, we have taken the approach of inducibly activating neuregulin signaling in these cells using transgenes in mice.…”

Section: Discussionmentioning

confidence: 95%

“…Previous work has shown that the Tet-On gene expression system can be used to conditionally regulate transgene expression in a variety of tissues (Mansuy et al, 1998;Xie et al, 1999;Chang et al, 2000;Diamond et al, 2000;Tichelaar et al, 2000;Liu et al, 2001;Moody et al, 2002;Ludwig et al, 2004;Suarez et al, 2004;Ponomareva et al, 2006). In these cases, a cell-specific promoter was used to drive expression of a transgene that codes for the transcription factor rtTA.…”

Section: Regulatory Elements Of the S100b Gene Confer Doxycyclineindumentioning

confidence: 99%

“…These results indicate that the S100 -rtTA transgenic mice provide an inducible regulation of the target transgene containing the mutant ErbB2 receptor that occurs within 3-5 d of administration of the inducer and that this induction is reversible. Although Ponomareva et al (2006) have used this same transgenic system to show that the induction of the luciferase reporter occurs at the same time as the levels of mutant ErbB2 and phospho-ErbB2 increase, there is no reason to believe the two will be linearly correlated, because one of the proteins is translated from an IRES and both proteins are likely to be degraded at different rates.…”

Section: A Mutant Constitutively Active Erbb2 Receptor Can Be Inducementioning

confidence: 99%

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Induction of Neuregulin Signaling in Mouse Schwann Cells In Vivo Mimics Responses to Denervation

Hayworth

Moody

Chodosh

et al. 2006

Journal of Neuroscience

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Neuregulins play crucial roles in early development of Schwann cells (SCs), but their roles in the activities of SCs during denervation and reinnervation of muscle are less clear. In the present study, the Tet-On system has been used in transgenic mice to enable inducible expression of a mutant, constitutively active neuregulin receptor (ErbB2) in SCs. This induction simulates neuregulin signaling to these cells. Reporter transgenes were used to show a tightly regulated, SC-selective expression in muscle. Induction leads to a number of changes in SCs at neuromuscular junctions that mimic the response to muscle denervation/reinnervation. These include process extension, soma migration, and proliferation. SCs also come to express nestin, a protein characteristic of their reaction to muscle denervation. This activation of SCs results in the sprouting of nerve terminals, and these sprouts follow the extensions of the SCs. However, these sprouts and their associated SCs disappear after the removal of the inducer. Last, induction of the active receptor is sufficient to rescue SCs in neonatal muscle from denervation-induced apoptosis. These findings show that the responses of SCs in muscle to denervation can be explained by induction of an autocrine/paracrine neuregulin signaling cascade suggested by previous molecular studies.

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Section: Discussionmentioning

confidence: 95%

Section: Regulatory Elements Of the S100b Gene Confer Doxycyclineindumentioning

confidence: 99%

Section: A Mutant Constitutively Active Erbb2 Receptor Can Be Inducementioning

confidence: 99%

See 1 more Smart Citation

Induction of Neuregulin Signaling in Mouse Schwann Cells In Vivo Mimics Responses to Denervation

Hayworth

Moody

Chodosh

et al. 2006

Journal of Neuroscience

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“…In skeletal muscle, nuclei located under the neuromuscular junction (NMJ) are uniquely regulated by neuregulin-stimulated Her2 signaling, which controls genes encoding proteins (e.g. acetylcholine receptor) that are required for NMJ integrity (Leu et al, 2003;Lin et al, 2000;Ponomareva et al, 2006;Vock et al, 2008;Yang et al, 2005). Both mice and patients with LMNA mutations have defective recruitment or retention of nuclei at the NMJ and misregulation of NMJ-specific genes (Mejat et al, 2009).…”

Section: Journal Of Cell Sciencementioning

confidence: 99%

Tyrosine phosphorylation of nuclear-membrane protein emerin by Src, Abl and other kinases

Tifft

Bradbury

Wilson

2009

Journal of Cell Science

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X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD) is caused by loss of emerin, a nuclear-membrane protein with roles in nuclear architecture, gene regulation and signaling. Phosphoproteomic studies have identified 13 sites of tyrosine phosphorylation in emerin. We validated one study, confirming that emerin is hyper-tyrosine-phosphorylated in Her2-overexpressing cells. We discovered that non-receptor tyrosine kinases Src and Abl each phosphorylate emerin and a related protein, LAP2, directly. Src phosphorylated emerin specifically at Y59, Y74 and Y95; the corresponding triple Yto-F ('FFF') mutation reduced tyrosine phosphorylation bỹ 70% in vitro and in vivo. Substitutions that removed a single hydroxyl moiety either decreased (Y19F, Y34, Y161F) or increased (Y4F) emerin binding to BAF in cells. Y19F, Y34F, Y161F and the FFF mutant also reduced recombinant emerin binding to BAF from HeLa lysates, demonstrating the involvement of both LEM-domain and distal phosphorylatable tyrosines in binding BAF. We conclude that emerin function is regulated by multiple tyrosine kinases, including Her2, Src and Abl, two of which (Her2, Src) regulate striated muscle. These findings suggest roles for emerin as a downstream effector and 'signal integrator' for tyrosine kinase signaling pathway(s) at the nuclear envelope.Key words: Emerin, LEM domain, Nuclear envelope, Emery-Dreifuss muscular dystrophy, Src, Her2, Abl, Barrier-to-autointegration factor (BAF), Cardiomyopathy, Breast cancer, Laminopathy, Neuromuscular junction Journal of Cell Science 3781 Emerin tyrosine phosphorylation receptor tyrosine kinases that can be activated by Her2 or other signaling pathways (Roskoski, 2005;Srinivasan and Plattner, 2006). We confirm Her2-stimulated emerin tyrosine phosphorylation and report that emerin and LAP2 are phosphorylated directly by Src and Abl. We also show that tyrosine phosphorylation of emerin regulates binding to BAF. ResultsWe compiled data from 13 independent proteomic studies (Amanchy et al., 2005;Brill et al., 2004;Cantin et al., 2008; Daub et al., 2008; Guo et al., 2008;Olsen et al., 2006;Pan et al., 2008;Rikova et al., 2007;Rush et al., 2005;Schlosser et al., 2006;Sui et al., 2008;Tao et al., 2005;Tsai et al., 2008), which identified 13 phosphorylated tyrosines in emerin (Fig. 1A). All sites except Y19 and Y41 were identified more than once. All 13 identified phosphorylated Tyr (Tyr-P) residues in human emerin are conserved in mouse, and six (corresponding to Y4, Y41, Y94, Y95, Y105, Y161) are conserved in Xenopus (Fig. 1B). These studies did not reveal responsible pathways or kinases.We validated tyrosine phosphorylation of emerin by immunoprecipitating endogenous emerin from HeLa cells treated with 1 M pervanadate (PV, a tyrosine phosphatase inhibitor) (Huyer et al., 1997) or buffer (PBS) as control, for 30 minutes before lysing cells. Emerin immunoprecipitated from PV-treated cells was specifically recognized by Tyr-P antibodies (not shown; see Fig. 2B). No other tyrosine-phosphorylated bands were dete...

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“…However, neuregulins might not be essential for synapse-specific transcription of AChR subunit genes because modest or no phenotypes were detected in mice lacking ErbB2/4 in skeletal muscle or neuregulin in motor neurons and muscle fibers (Escher et al, 2005;Jaworski and Burden, 2006). Other data suggest that the primary role of neuregulins on the postsynaptic side is involved in regulating clustering and trafficking of AChRs to the surface of cells (Trinidad and Cohen, 2004;Ponomareva et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Identification of Erbin Interlinking MuSK and ErbB2 and Its Impact on Acetylcholine Receptor Aggregation at the Neuromuscular Junction

Simeone¹,

Straubinger²,

Khan³

et al. 2010

J. Neurosci.

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Defective neuromuscular synaptogenesis in mice expressing constitutively active ErbB2 in skeletal muscle fibers

Cited by 23 publications

References 52 publications

Induction of Neuregulin Signaling in Mouse Schwann Cells In Vivo Mimics Responses to Denervation

Induction of Neuregulin Signaling in Mouse Schwann Cells In Vivo Mimics Responses to Denervation

Tyrosine phosphorylation of nuclear-membrane protein emerin by Src, Abl and other kinases

Identification of Erbin Interlinking MuSK and ErbB2 and Its Impact on Acetylcholine Receptor Aggregation at the Neuromuscular Junction

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