Lrp4 is a receptor for Agrin and forms a complex with MuSK
Open accessAbstract
Neuromuscular synapse formation requires a complex exchange of signals between motor neurons and skeletal muscle fibers, leading to the accumulation of postsynaptic proteins, including acetylcholine receptors in the muscle membrane and specialized release sites, or active zones in the presynaptic nerve terminal. MuSK, a receptor tyrosine kinase that is expressed in skeletal muscle, and Agrin, a motor neuron-derived ligand that stimulates MuSK phosphorylation, play critical roles in synaptic differentiation, as synapses do not form in their absence, and mutations in MuSK or downstream effectors are a major cause of a group of neuromuscular disorders, termed congenital myasthenic syndromes (CMS). How Agrin activates MuSK and stimulates synaptic differentiation is not known and remains a fundamental gap in our understanding of signaling at neuromuscular synapses. Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Agrin released from motor neurons signals through APP, MuSK, and Lrp4 to recruit nicotinic acetylcholine receptors.
“Agrin is released from the motor neuron and signals through APP, MuSK and Lrp4 to recruit nicotinic acetylcholine receptors (AChRs).”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [89]
At the neuromuscular junction, Lrp4, APP, and MuSK form a complex that prepatterns the muscle.
“at the NMJ, Lrp4, APP and muscle-specific kinase (MuSK) form a complex to prepattern the muscle [88–90]”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [89]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Brown, M. S., & Goldstein, J. L. (1997) · Cell · doi:10.1016/s0092-8674(00)80213-5 · Cited by 3,834 · see citing works
The Immunological Synapse: A Molecular Machine Controlling T Cell Activation
Grakoui, A., Bromley, S. K., Sumen, C., Davis, M. M., Shaw, A. S., Allen, P. M., & Dustin, M. L. (1999) · Science · doi:10.1126/science.285.5425.221 · Cited by 3,110 · see citing works
Self-citationOosterhuis, H. (1997) · Cited by 2,404 · see citing works
Induction, assembly, maturation and maintenance of a postsynaptic apparatus
Sanes, J. R., & Lichtman, J. W. (2001) · Nature reviews. Neuroscience · doi:10.1038/35097557 · Cited by 1,025 · see citing works
The Receptor Tyrosine Kinase MuSK Is Required for Neuromuscular Junction Formation In Vivo
DeChiara, T. M., Bowen, D. C., Valenzuela, D. M., Simmons, M. V., Poueymirou, W. T., Thomas, S., Kinetz, E., Compton, D. L., Rojas, E., Park, J. S., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81251-9 · Cited by 912 · see citing works
Self-citationAn adaptive coding model of neural function in prefrontal cortex
Duncan, J. (2001) · UCL Discovery (University College London) · Cited by 738 · see citing works
Agrin Acts via a MuSK Receptor Complex
Glass, D. J., Bowen, D. C., Stitt, T. N., Radziejewski, C. H., Bruno, J., RYAN, T. E., Gies, D. R., Shah, S., Mattsson, K., Burden, S. J., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81252-0 · Cited by 662 · see citing works
Self-citationNeuromuscular Junction in Myasthenia Gravis: Decreased Acetylcholine Receptors
Fambrough, D. M., Drachman, D. B., & Satya‐Murti, S. (1973) · Science · doi:10.1126/science.182.4109.293 · Cited by 641 · see citing works
Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse
Lin, W., Burgess, R. W., Dominguez, B., Pfaff, S. L., Sanes, J. R., & Lee, K. (2001) · Nature · doi:10.1038/35074025 · Cited by 534 · see citing works
Dystroglycan-α, a dystrophin-associated glycoprotein, is a functional agrin receptor
Gee, S., Montanaro, F., Lindenbaum, M., & Carbonetto, S. (1994) · Cell · doi:10.1016/0092-8674(94)90052-3 · Cited by 512 · see citing works
The Muscle Protein Dok-7 Is Essential for Neuromuscular Synaptogenesis
Okada, K., Inoue, A., Okada, M., et al. (2006) · Science · doi:10.1126/science.1127142 · Cited by 440 · see citing works
Valenzuela, D. M., Stitt, T. N., DiStefano, P. S., Rojas, E., Mattsson, K., Compton, D. L., Nuñez, L., Park, J. S., Stark, J. L., Gies, D. R., et al. (1995) · Neuron · doi:10.1016/0896-6273(95)90146-9 · Cited by 417 · see citing works
Self-citationA role for dystrophin-associated glycoproteins and utrophin in agrin-induced AChR clustering
Campanelll, J. T., Roberds, S. L., Campbell, K. P., & Scheller, R. H. (1994) · Cell · doi:10.1016/0092-8674(94)90051-5 · Cited by 369 · see citing works
LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction
Weatherbee, S. D., Anderson, K. V., & Niswander, L. A. (2006) · Development · doi:10.1242/dev.02696 · Cited by 351 · see citing works
Bowe, M. A., Deyst, K. A., Leszyk, J., & Fallon, J. R. (1994) · Neuron · doi:10.1016/0896-6273(94)90324-7 · Cited by 307 · see citing works
Ferns, M., Campanelli, J. T., Hoch, W., Scheller, R. H., & Hall, Z. W. (1993) · Neuron · doi:10.1016/0896-6273(93)90153-i · Cited by 306 · see citing works
Assembly of the postsynaptic membrane at the neuromuscular junction: paradigm lost
Kummer, T. T., Misgeld, T., & Sanes, J. R. (2005) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2005.12.003 · Cited by 291 · see citing works
Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site.
Gesemann, M., Denzer, A. J., & Ruegg, M. A. (1995) · The Journal of cell biology · doi:10.1083/jcb.128.4.625 · Cited by 236 · see citing works
Interference reflection microscopy in cell biology: methodology and applications
Verschueren, H. (1985) · Journal of Cell Science · doi:10.1242/jcs.75.1.279 · Cited by 234 · see citing works
MuSK controls where motor axons grow and form synapses
Kim, N., & Burden, S. J. (2007) · Nature Neuroscience · doi:10.1038/nn2026 · Cited by 197 · see citing works
Self-citationThe formation of neuromuscular synapsesPreprint
Burden, S. J. (1998) · Genes & Development · doi:10.1101/gad.12.2.133 · Cited by 188 · see citing works
Self-citationThe juxtamembrane region of MuSK has a critical role in agrin‐mediated signaling
Herbst, R., & Burden, S. J. (2000) · The EMBO Journal · doi:10.1093/emboj/19.1.67 · Cited by 167 · see citing works
Self-citationCurrent understanding of congenital myasthenic syndromes
Engel, A. G., & Sine, S. M. (2005) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.12.007 · Cited by 159 · see citing works
Vincent, A. C., & Leite, M. I. (2005) · Current Opinion in Neurology · doi:10.1097/01.wco.0000180660.57801.3f · Cited by 149 · see citing works
Zhou, H. H., Glass, D. J., Yancopoulos, G. D., & Sanes, J. R. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.146.5.1133 · Cited by 145 · see citing works
Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice
Johnson, E. B., Hammer, R. E., & Herz, J. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi381 · Cited by 141 · see citing works
α3Na+/K+-ATPase Is a Neuronal Receptor for Agrin
Hilgenberg, L. G. W., Su, H., Gu, H., O’Dowd, D. K., & Smith, M. A. (2006) · Cell · doi:10.1016/j.cell.2006.01.052 · Cited by 126 · see citing works
Synapse Loss in Cortex of Agrin-Deficient Mice after Genetic Rescue of Perinatal Death
Ksiazek, I., Burkhardt, C., Lin, S., Seddik, R., Maj, M., Bezáková, G., Jucker, M., Arber, S., Caroni, P., Sanes, J. R., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1609-07.2007 · Cited by 115 · see citing works
García‐Osta, A., Tsokas, P., Pollonini, G., Landau, E. M., Blitzer, R. D., & Alberini, C. M. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.1674-06.2006 · Cited by 92 · see citing works
Simon, A. M., & Burden, S. J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.9.5133 · Cited by 87 · see citing works
Self-citationSequential roles of agrin, MuSK and rapsyn during neuromuscular junction formation
Glass, D. J., & Yancopoulos, G. D. (1997) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(97)80066-9 · Cited by 78 · see citing works
Intracellular Calcium Regulates Agrin-Induced Acetylcholine Receptor Clustering
Megeath, L. J., & Fallon, J. R. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-02-00672.1998 · Cited by 75 · see citing works
Dustin, M. L. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.25.15782 · Cited by 72 · see citing works
Self-citationStiegler, A. L., Burden, S. J., & Hubbard, S. R. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.09.019 · Cited by 69 · see citing works
Self-citationDrögemüller, C., Leeb, T., Harlizius, B., Tammen, I., Distl, O., Höltershinken, M., Gentile, A., Duchesne, A., & Eggen, A. (2007) · BMC Genetics · doi:10.1186/1471-2156-8-5 · Cited by 60 · see citing works
Jacobson, C., Montanaro, F., Lindenbaum, M., Carbonetto, S., & Ferns, M. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-16-06340.1998 · Cited by 60 · see citing works
Dystrophin-associated proteins and synapse formation: Is α-dystroglycan the agrin receptor?
Sealock, R. W., & Froehner, S. C. (1994) · Cell · doi:10.1016/0092-8674(94)90045-0 · Cited by 59 · see citing works
Arber, S., Burden, S. J., & Harris, A. (2002) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(02)00296-9 · Cited by 58 · see citing works
Self-citationTian, Q., Suzuki, T., Yamauchi, T., Sakagami, H., Yoshimura, Y., Miyazawa, S., Nakayama, K., Saitoh, F., Zhang, J., Lu, Y., et al. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.04846.x · Cited by 56 · see citing works
A Single Pulse of Agrin Triggers a Pathway That Acts To Cluster Acetylcholine Receptors
Mittaud, P., Camilleri, A., Willmann, R., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.18.7841-7854.2004 · Cited by 52 · see citing works
Kleiman, R. J., & Reichardt, L. F. (1996) · Cell · doi:10.1016/s0092-8674(00)81245-3 · Cited by 48 · see citing works
Meier, T., Gesemann, M., Cavalli, V., Rüegg, M. A., & Wallace, B. G. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00622.x · Cited by 41 · see citing works
Glass, D. J., DeChiara, T. M., Stitt, T. N., et al. (1996) · PubMed · Cited by 41 · see citing works
Hopf, C., & Hoch, W. (1998) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1998.2530382.x · Cited by 34 · see citing works
Further Observations in Congenital Myasthenic Syndromes
Engel, A. G., Shen, X., Selcen, D., et al. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1405.039 · Cited by 31 · see citing works
Dual role for calcium in agrin signaling and acetylcholine receptor clustering
Borges, L. S., Lee, Y. I., & Ferns, M. (2001) · Journal of Neurobiology · doi:10.1002/neu.10020 · Cited by 30 · see citing works
Congenital Myasthenic Syndromes and the Formation of the Neuromuscular Junction
Beeson, D., Webster, R. G., Cossins, J., et al. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1405.049 · Cited by 30 · see citing works
Dustin, M. L., Starr, T., Coombs, D., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705616200 · Cited by 25 · see citing works
Self-citationVincent, A. C., & Drachman, D. B. (2002) · PubMed · Cited by 18 · see citing works
Simon, A. M., & Burden, S. J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.9.5133-5140.1993 · Cited by 15 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168 · see citing works
The dual role of the extracellular matrix in synaptic plasticity and homeostasis
Dityatev, A., Schachner, M., & Sonderegger, P. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2898 · Cited by 559 · see citing works
The gut microbiota influences skeletal muscle mass and function in mice
Lahiri, S., Kim, H., Garcia-Perez, I., Reza, M. M., Martin, K. A., Kundu, P., Cox, L. M., Selkrig, J., Posma, J. M., Zhang, H., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aan5662 · Cited by 580 · see citing works
Extracellular Matrix: Functions in the Nervous System
Barros, C. S., Franco, S. J., & Muller, U. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005108 · Cited by 506 · see citing works
Skeletal muscle tissue engineering: methods to form skeletal myotubes and their applications
Ostrovidov, S., Hosseini, V., Ahadian, S., Fujie, T., Parthiban, S. P., Ramalingam, M., Bae, H., Kaji, H., & Khademhosseini, A. (2014) · Tissue Engineering Part B: Reviews · doi:10.1089/ten.teb.2013.0534 · Cited by 302 · see citing works
TGF-β family co-receptor function and signaling
Nickel, J., Ten Dijke, P., & Mueller, T. D. (2018) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmx126 · Cited by 198 · see citing works
Li, Y., Pawlik, B., Elcioglu, N., Aglan, M., Kayserili, H., Yigit, G., Percin, F., Goodman, F., Nürnberg, G., Cenani, A., et al. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.03.004 · Cited by 171 · see citing works
Shaping Synapses by the Neural Extracellular Matrix
Ferrer-Ferrer, M., & Dityatev, A. (2018) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2018.00040 · Cited by 169 · see citing works
ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease
Lane-Donovan, C., & Herz, J. (2017) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.12.001 · Cited by 157 · see citing works
More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration
Lane-Donovan, C., Philips, G. T., & Herz, J. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.005 · Cited by 158 · see citing works
Lrp4 in astrocytes modulates glutamatergic transmission
Sun, X.-D., Li, L., Liu, F., Huang, Z.-H., Bean, J. C., Jiao, H.-F., Barik, A., Kim, S.-M., Wu, H., Shen, C., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4326 · Cited by 102 · see citing works
“(p) Quantitative analysis of LTP level in o (n = 8 slices from 4 control mice; n = 7 from 4 GFAP-CreER;Lrp4−/− mice; Student’s t test, t(13) = 2.”
BackgroundMethodInfluentialRuggiu, M., Herbst, R., Kim, N., Jevsek, M., Fak, J. J., Mann, M. A., Fischbach, G., Burden, S. J., & Darnell, R. B. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813112106 · Cited by 113 · see citing works
Self-citationFunctional Roles of the Interaction of APP and Lipoprotein Receptors
Pohlkamp, T., Wasser, C. R., & Herz, J. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00054 · Cited by 92 · see citing works
Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease
Xian, X., Pohlkamp, T., Durakoglugil, M. S., Wong, C. H., Beck, J. K., Lane-Donovan, C., Plattner, F., & Herz, J. (2018) · eLife · doi:10.7554/elife.40048 · Cited by 98 · see citing works
Choi, H. Y., Liu, Y., Tennert, C., Sugiura, Y., Karakatsani, A., Kröger, S., Johnson, E. B., Hammer, R. E., Lin, W., & Herz, J. (2013) · eLife · doi:10.7554/elife.00220 · Cited by 71 · see citing works
Selcen, D., Ohkawara, B., Shen, X.-M., McEvoy, K., Ohno, K., & Engel, A. G. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2015.0853 · Cited by 53 · see citing works
Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4
Gomez, A. M., Froemke, R. C., & Burden, S. J. (2014) · eLife · doi:10.7554/elife.04287 · Cited by 47 · see citing works
Self-citationLrp4 domains differentially regulate limb/brain development and synaptic plasticity
Pohlkamp, T., Durakoglugil, M., Lane-Donovan, C., Xian, X., Johnson, E. B., Hammer, R. E., & Herz, J. (2015) · PLOS ONE · doi:10.1371/journal.pone.0116701 · Cited by 28 · see citing works
Kurgan, N., Stoikos, J., Baranowski, B. J., Yumol, J., Dhaliwal, R., Sweezey-Munroe, J. B., Fajardo, V. A., Gittings, W., Macpherson, R. E. K., & Klentrou, P. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4768 · Cited by 12 · see citing works
- Authors
- Kim, N., Stiegler, A. L., Cameron, T. O., Hallock, P. T., Gomez, A. M., Huang, J. H., Hubbard, S. R., Dustin, M. L., & Burden, S. J.
- Affiliations
- NYU Langone Health (US)
- Corresponding author
- Burden, Steven J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 135
- Issue
- 2
- Pages
- 334-342
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2933840
- OpenAlex
- W1984522719
- Cited by
- 676
- References
- 50
- Citations by year
- 2026: 29 · 2025: 37 · 2024: 35 · 2023: 24 · 2022: 34 · 2021: 31 · 2020: 51 · 2019: 39 · 2018: 35 · 2017: 37 · 2016: 36 · 2015: 33 · 2014: 39 · 2013: 51 · 2012: 49
- FWCI
- 24.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1750 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA016087)
- National Institute of General Medical Sciences (R21GM075180)
- National Institute of Neurological Disorders and Stroke (R01NS053414, R37NS036193, R01NS036193, NS53414)
- Topics
- Health Sciences › Medicine › Neurology › Myasthenia Gravis and Thymoma
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- LRP4, agrin, musk, neuromuscular synapse formation, synaptic differentiation, receptor tyrosine kinase, congenital myasthenic syndrome, postsynaptic proteins
- MeSH terms
- Animals, Cell Line, Models, Biological, Neuromuscular Junction, Phosphorylation, Receptors, LDL, Agrin, Receptor Protein-Tyrosine Kinases, LDL-Receptor Related Proteins, Myoblasts, Mice, Precursor Cells, B-Lymphoid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
