Receptor tyrosine kinase specific for the skeletal muscle lineage: Expression in embryonic muscle, at the neuromuscular junction, and after injury

Valenzuela, David M.; Stitt, Trevor N.; DiStefano, Peter S.; Rojas, Eduardo; Mattsson, Karen; Compton, Debra L; Nuñez, Lorna; Park, John S.; Stark, Jennifer; Gies, David R.; Thomas, Susan E.; Beau, Michelle M. Le; Fernald, Anthony A.; Copeland, Neal G.; Jenkins, Nancy A.; Burden, Steven J.; Glass, David J.; Yancopouloš, George D.

doi:10.1016/0896-6273(95)90146-9

Cited by 397 publications

(386 citation statements)

References 33 publications

Supporting

Mentioning

353

Contrasting

Unclassified

Order By: Relevance

“…In wild-type mice, Musk mRNA and protein are concentrated at neuromuscular synapses (Valenzuela et al, 1995). In Musk mutant mice carrying MCK-Musk, Musk mRNA is expressed throughout the muscle, yet Musk protein is concentrated at synaptic sites.…”

Section: Discussionmentioning

confidence: 99%

“…In wild-type mice, Musk RNA, like AChR mRNA, is expressed preferentially at synaptic sites (Valenzuela et al, 1995). Because the MCK gene is expressed in nuclei throughout the myofiber (Tang et al, 1994), the MCK regulatory region, as expected, confers Musk and MMT mRNA expression uniformly throughout the muscle (Fig.…”

Section: Musk and Mmt Proteins Are Concentrated At Synaptic Sites Desmentioning

confidence: 94%

See 1 more Smart Citation

Restoration of synapse formation inMuskmutant mice expressing a Musk/Trk chimeric receptor

Herbst

Avetisova²,

Burden³

2002

Development

Self Cite

View full text Add to dashboard Cite

Development 129, [5449][5450][5451][5452][5453][5454][5455][5456][5457][5458][5459][5460] On page 5454 of this article, the first paragraph in the section 'Motor axons extend…' should read 'Based on the expression of transgenes containing the MCK enhancer and promoter, the endogenous MCK gene is activated in skeletal muscle at ~E13.5 (S. Hauschka, personal communication), 1 day after motor axons first enter the muscle.'We apologise to the authors and readers for this mistake. ERRATUM INTRODUCTIONNeuromuscular synapses form following a series of complex interactions between motor neurons, muscle fibers and Schwann cells (Burden, 1998;Sanes and Lichtman, 1999;Schaeffer et al., 2001;Son and Thompson, 1995). Agrin, a 200 kDa protein synthesized by motor neurons, is a critical synaptic signaling molecule that organizes postsynaptic differentiation by stimulating Musk, a receptor tyrosine kinase (RTK) expressed selectively in skeletal muscle McMahan, 1990). Embryos lacking agrin or Musk fail to form neuromuscular synapses and consequently die at birth due to their failure to move or breathe (DeChiara et al., 1996;Gautam et al., 1996). Neurogenesis and myogenesis appear normal in agrin and Musk mutant embryos, but skeletal muscle-derived proteins, including acetylcholine receptors (AChRs), which are normally concentrated at synaptic sites, are instead expressed uniformly in muscle of Musk mutant mice. In addition, AChR genes, which are transcribed selectively in synaptic nuclei of wild-type mice, are expressed throughout the myofiber of Musk mutant mice. Presynaptic differentiation is also aberrant in agrin and Musk mutant mice, as motor axons fail to stop or differentiate and instead wander throughout the muscle. Taken together with experiments showing that Musk is activated by agrin, these results indicate that agrin stimulation of Musk leads to clustering of critical musclederived proteins, including AChRs, activation of synapsespecific gene expression and the induction and/or reorganization of a retrograde signal for presynaptic differentiation (DeChiara et al., 1996;Gautam et al., 1996;Glass et al., 1996). Domains in Musk that are important for Musk signaling have been defined by introducing wild-type or mutant forms of Musk into Musk mutant muscle cell lines (Herbst and Burden, 2000;Zhou et al., 1999). These studies have revealed an essential role for one of the two juxtamembrane tyrosine residues in Musk (Y553), as mutation of this tyrosine abrogates the ability of agrin to induce clustering or tyrosine phosphorylation of AChRs in cultured myotubes. This tyrosine appears to have a dual function in Musk signaling, as this tyrosine is required both to activate Musk kinase activity fully and to recruit a signaling component(s) that functions downstream from Musk (Herbst and Burden, 2000). Evidence for such a dual role is based upon analysis of Musk/TrkA chimeric receptors. Agrin stimulates tyrosine phosphorylation of a chimeric receptor composed of the extracellular and transmembrane regions of Musk, and the intrac...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Musk and Mmt Proteins Are Concentrated At Synaptic Sites Desmentioning

confidence: 94%

Restoration of synapse formation inMuskmutant mice expressing a Musk/Trk chimeric receptor

Herbst

Avetisova²,

Burden³

2002

Development

Self Cite

View full text Add to dashboard Cite

show abstract

“…These studies implicated motor neuron-derived Agrin, a glycosylated proteoglycan, as the critical neural signal for inducing postsynaptic differentiation and the muscle-specific receptor tyrosine kinase, MuSK, a component of the Agrin receptor, as the transducer for clustering AChRs and activating AChR gene expression at synaptic sites (Burden, 1998;Glass et al, 1996a;Glass et al, 1996b;Glass and Yancopoulos, 1997;Sanes and Lichtman, 2001;Schaeffer et al, 2001;Valenzuela et al, 1995). This neuro-centric view of neuromuscular synapse formation, however, has been challenged by recent experiments, which showed that mammalian muscle is spatially patterned independent of innervation.…”

Section: Introductionmentioning

confidence: 99%

MuSK controls where motor axons grow and form synapses

2007

View full text Add to dashboard Cite

SummaryIt had long been thought that motor axons approach muscles that are regionally unspecialized and induce postsynaptic differentiation by releasing signals that focally initiate transcriptional and post-translational responses in muscle. This neuro-centric view of synapse formation, however, has been challenged by recent experiments, which showed that AChR clusters are concentrated in the central region of muscle independent of innervation. This nerve-independent prepattern of AChR expression requires MuSK, a receptor tyrosine kinase that is critical for synapse formation. How muscle prepatterning is established and whether motor axons recognize this prepattern are not known. Here, we show that MuSK itself is prepatterned in muscle and that high, ectopic MuSK expression is sufficient to promote ectopic motor axon growth and synapse formation, indicating that the muscle prepattern is recognized by motor axons and promotes synapse formation in the central region of developing mammalian muscle. Further, we provide evidence that early expression of MuSK in developing myotubes is sufficient to re-establish muscle prepatterning independent of the MuSK promoter. Moreover, we show that ectopic MuSK expression stimulates synapse formation in the absence of Agrin and rescues the neonatal lethality of agrin mutant mice, demonstrating that MuSK, independent of Agrin, is sufficient to direct presynaptic and postsynaptic differentiation. In contrast to a neuro-centric view for synapse formation, these data demonstrate that the postsynaptic cell can play a dominant role in regulating synapse formation.

show abstract

“…Mammalian Ror2 and the closely related paralog Ror1 belong to a small family of receptor tyrosine kinases (RTKs) that have been characterized by their homology to MuSK and TrkRTKs (Masiakowski and Carroll, 1992;Valenzuela et al, 1995). Ror2 possesses an intracellular tyrosine kinase domain and a C-terminal proline-serine-threonine-rich (PST) domain.…”

Section: Introductionmentioning

confidence: 99%

Cloning and expression pattern of chicken Ror2 and functional characterization of truncating mutations in Brachydactyly type B and Robinow syndrome

Stricker

Wijk

Witte

et al. 2006

Developmental Dynamics

View full text Add to dashboard Cite

Ror2 is a receptor tyrosine kinase mutated in the human syndromes Brachydactyly type B (BDB) and recessive Robinow syndrome (RS). In this study, we used the chick as a model to investigate the role of Ror2 in skeletogenesis and to elucidate the functional consequences of Ror2 mutations. For this purpose, we cloned chicken Ror2 and analyzed its expression pattern at various embryonic stages by in situ hybridization and immunolabeling. We document expression of cRor2 in several organs, including mesonephros, heart, nervous system, intestine and cartilage.

show abstract

Receptor tyrosine kinase specific for the skeletal muscle lineage: Expression in embryonic muscle, at the neuromuscular junction, and after injury

Cited by 397 publications

References 33 publications

Restoration of synapse formation inMuskmutant mice expressing a Musk/Trk chimeric receptor

Restoration of synapse formation inMuskmutant mice expressing a Musk/Trk chimeric receptor

MuSK controls where motor axons grow and form synapses

Cloning and expression pattern of chicken Ror2 and functional characterization of truncating mutations in Brachydactyly type B and Robinow syndrome

Contact Info

Product

Resources

About