Neuregulin-2 is synthesized by motor neurons and terminal Schwann cells and activates acetylcholine receptor transcription in muscle cells expressing ErbB4

Rimer, Mendell; Prieto, Anne L.; Weber, Janet L.; Colasante, Cesare; Ponomareva, Olga N.; Fromm, Larry; Schwab, Markus H.; Lai, Cary; Burden, Steven J.

doi:10.1016/j.mcn.2004.02.002

Cited by 40 publications

(49 citation statements)

References 39 publications

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“…We cannot distinguish expression from terminal Schwann cells and myofiber synaptic nuclei by in situ hybridization of muscle whole mounts (12). Thus, our in situ hybridization data are consistent with the possibility that CD24 is expressed in terminal Schwann cells or in myofiber synaptic nuclei.…”

Section: Cd24 Is Expressed Preferentially By Myofiber Synaptic Nucleisupporting

confidence: 67%

CD24 is expressed by myofiber synaptic nuclei and regulates synaptic transmission

Jevsek

Jaworski

Polo‐Parada

et al. 2006

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

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The genes encoding several synaptic proteins, including acetylcholine receptors, acetylcholinesterase, and the muscle-specific kinase, MuSK, are expressed selectively by a small number of myofiber nuclei positioned near the synaptic site. Genetic analysis of mutant mice suggests that additional genes, expressed selectively by synaptic nuclei, might encode muscle-derived retrograde signals that regulate the differentiation of motor axon terminals. To identify candidate retrograde signals, we used a microarray screen to identify genes that are preferentially expressed in the synaptic region of muscle, and we analyzed one such gene, CD24, further. We show that CD24, which encodes a small, variably and highly glycosylated, glycosylphosphatidylinositol (GPI)-linked protein, is expressed preferentially by myofiber synaptic nuclei in embryonic and adult muscle, and that CD24 expression is restricted to the central region of muscle independent of innervation. Moreover, we show that CD24 has a role in presynaptic differentiation, because synaptic transmission is depressed and fails entirely, in a cyclical manner, after repetitive stimulation of motor axons in CD24 mutant mice. These deficits in synaptic transmission, which are accompanied by aberrant stimulus-dependent uptake of AM1-43 from axons, indicate that CD24 is required for normal presynaptic maturation and function. Because CD24 is also expressed in some neurons, additional experiments will be required to determine whether pre-or postsynaptic CD24 mediates these effects on presynaptic development and function.heat-stable antigen ͉ neuromuscular synapses ͉ P-selectin ͉ synapse-specific transcription N early one dozen genes, including those encoding acetylcholine receptors (AChRs), acetylcholinesterase (AChE), muscle-specific kinase (MuSK), and utrophin, are expressed selectively by a small number of myofiber nuclei positioned near the synaptic site (1-5). This pattern of gene expression depends on MuSK, a muscle-specific receptor tyrosine kinase that is activated by neurally derived agrin, because ''synapse-specific'' genes are expressed uniformly in muscle from MuSK mutant mice (6). In addition, presynaptic differentiation is MuSKdependent, because motor axons fail to stop and differentiate in agrin or MuSK mutant mice (6, 7). Because MuSK is required for synapse-specific transcription and presynaptic differentiation, these findings raise the possibility that muscle-derived signals, which cause motor axons to stop growing and differentiate, may be expressed preferentially by myofiber synaptic nuclei.Among the known synapse-specific genes, AChR, AChE, MuSK, NCAM, and S-laminin encode for cell surface proteins, suggesting that these proteins could, in principle, function as retrograde signals (1-3, 5, 8). It seems likely, however, that additional genes, encoding cell surface proteins, are transcribed preferentially by myofiber synaptic nuclei. In mammalian muscle, neuromuscular synapses are confined to a narrow zone, near the center of the muscle. As such, the syn...

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Section: Cd24 Is Expressed Preferentially By Myofiber Synaptic Nucleisupporting

confidence: 67%

CD24 is expressed by myofiber synaptic nuclei and regulates synaptic transmission

Jevsek

Jaworski

Polo‐Parada

et al. 2006

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

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“…Western blotting was done as previously described (19). 75 g of protein/sample were separated in 10% denaturing polyacrylamide gels.…”

Section: Methodsmentioning

confidence: 99%

Modulation of Agrin-induced Acetylcholine Receptor Clustering by Extracellular Signal-regulated Kinases 1 and 2 in Cultured Myotubes

Rimer

2010

Journal of Biological Chemistry

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Agrin released by motoneurons induces and/or maintains acetylcholine receptor (AChR) clustering and other aspects of postsynaptic differentiation at the vertebrate neuromuscular junction. Agrin acts by binding and activating a receptor complex containing LDL receptor protein 4 (Lrp4) and muscle-specific kinase (MuSK). Two critical downstream components of this signaling cascade, Dox-7 and rapsyn, have been identified. However, additional intracellular essential elements remain unknown. Prior observations by others and us suggested antagonistic interactions between agrin and neuregulin-1 (Nrg-1) signaling in cultured myotubes and developing muscle fibers in vivo. A hallmark of Nrg-1 signaling in skeletal muscle cells is the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). ERK1/2 are also activated in most cells by phorbol 12-myristate 13-acetate, a classical inhibitor of agrin-induced AChR clustering in myotubes. Here, it was investigated whether agrin activates ERK1/2 directly and whether such activation modulates agrin-induced AChR clustering. Agrin induced a rapid but transient activation of ERK1/2 in myotubes that was Lrp4/MuSK-dependent. However, blocking this ERK1/2 activation did not prevent but potentiated AChR clustering induced by agrin. ERK1/2 activation was dispensable for Nrg-1-mediated inhibition of the AChR clustering activity of agrin, but was indispensable for such activity by phorbol 12-myristate 13-acetate. Together, these results suggest agrin-induced activation of ERK1/2 is a negative modulator of agrin signaling in skeletal muscle cells.For more than a decade, three proteins have stood out as the essential signaling partners in vertebrate neuromuscular junction (NMJ) 2 synaptogenesis. Agrin, a proteoglycan released by motoneurons that induces and/or maintains acetylcholine receptor (AChR) clustering and other aspects of postsynaptic differentiation (1). MuSK, a receptor tyrosine kinase activated by agrin (2, 3); and rapsyn, an intracellular peripheral membrane protein that binds to AChRs (4, 5). Recently, two additional key components of this signaling pathway have been discovered: Lpr4, a LDL-like receptor protein that binds agrin and associates with MuSK (6, 7); and Dok-7 (8), a phosphotyrosinebinding protein that binds to activated MuSK. In the absence of any of these proteins, neuromuscular synapses simply fail to form in vivo (8 -12). Despite this impressive progress, how agrin-induced MuSK activation leads to AChR clustering remains elusive as additional critical intracellular components of the core pathway are yet to be identified.Previously, Trinidad and Cohen (13) showed that in cultured myotubes agrin-induced AChR clustering was inhibited by cotreatment with Nrg-1. We showed that agrin failed to cluster AChRs in cultured myotubes expressing a constitutively active neuregulin receptor ErbB2 (14). Importantly, when expressed in developing muscle fibers in vivo, constitutively active ErbB2 led to synaptic loss resembling the neuromuscular phenotype in mice defici...

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“…In situ hybridization with digoxigenin-labeled riboprobes was performed as described previously (Rimer et al, 2004). The nestin probe was generated by PCR using adult rat skeletal muscle cDNA as template.…”

Section: Methodsmentioning

confidence: 99%

“…T3 RNA polymerase was used to make antisense probes; T7 RNA polymerase was used to make sense probes. The probe for AChR␣ was described previously (Rimer et al, 2004). Cholinesterase activity was visualized by histochemical staining (Karnovsky, 1964).…”

Section: Methodsmentioning

confidence: 99%

Regulation of the Intermediate Filament Protein Nestin at Rodent Neuromuscular Junctions by Innervation and Activity

Kang

Tian²,

Son³

et al. 2007

J. Neurosci.

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The intermediate filament nestin is localized postsynaptically at rodent neuromuscular junctions. The protein forms a filamentous network beneath and between the synaptic gutters, surrounds myofiber nuclei, and is associated with Z-discs adjacent to the junction. In situ hybridization shows that nestin mRNA is synthesized selectively by synaptic myonuclei. Although weak immunoreactivity is present in myelinating Schwann cells that wrap the preterminal axon, nestin is not detected in the terminal Schwann cells (tSCs) that cover the nerve terminal branches. However, after denervation of muscle, nestin is upregulated in tSCs and in SCs within the nerve distal to the lesion site. In contrast, immunoreactivity is strongly downregulated in the muscle fiber. Transgenic mice in which the nestin neural enhancer drives expression of a green fluorescent protein (GFP) reporter show that the regulation in SCs is transcriptional. However, the postsynaptic expression occurs through enhancer elements distinct from those responsible for regulation in SCs. Application of botulinum toxin shows that the upregulation in tSCs and the loss of immunoreactivity in muscle fibers occurs with blockade of transmitter release. Extrinsic stimulation of denervated muscle maintains the postsynaptic expression of nestin but does not affect the upregulation in SCs. Thus, a nestin-containing cytoskeleton is promoted in the postsynaptic muscle fiber by nerve-evoked muscle activity but suppressed in tSCs by transmitter release. Nestin antibodies and GFP driven by nestin promoter elements serve as excellent markers for the reactive state of SCs. Vital imaging of GFP shows that SCs grow a dynamic set of processes after denervation.

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Neuregulin-2 is synthesized by motor neurons and terminal Schwann cells and activates acetylcholine receptor transcription in muscle cells expressing ErbB4

Cited by 40 publications

References 39 publications

CD24 is expressed by myofiber synaptic nuclei and regulates synaptic transmission

CD24 is expressed by myofiber synaptic nuclei and regulates synaptic transmission

Modulation of Agrin-induced Acetylcholine Receptor Clustering by Extracellular Signal-regulated Kinases 1 and 2 in Cultured Myotubes

Regulation of the Intermediate Filament Protein Nestin at Rodent Neuromuscular Junctions by Innervation and Activity

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