The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Rescuing Z + agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing
Open accessAbstract
Synapse formation at the neuromuscular junction (NMJ) requires an alternatively spliced variant of agrin (Z + agrin) that is produced only by neurons. Here, we show that Nova1 and Nova2, neuron-specific splicing factors identified as targets in autoimmune motor disease, are essential regulators of Z + agrin. Nova1 / Nova2 double knockout mice are paralyzed and fail to cluster AChRs at the NMJ, and breeding them with transgenic mice constitutively expressing Z + agrin in motor neurons rescued AChR clustering. Surprisingly, however, these rescued mice remained paralyzed, while electrophysiologic studies demonstrated that the motor axon and synapse were functional-spontaneous and evoked recordings revealed synaptic transmission and muscle contraction. These results point to a proximal defect in motor neuron firing in the absence of Nova and reveal a previously unsuspected role for RNA regulation in the physiologic activation of motor neurons.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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?
In the citing paper
“The paralysis phenotype and early mortality are unchanged by the transgene, indicating the contributions of additional NOVA targets, possibly in other brain regions.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [73]
In the citing paper
“restoring Z+ Agrn expression in dKO motor neurons via a transgene rescues AchR clustering, nerve terminal apposition, NMJ morphology and muscle responses to stimuli73.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [73]
In the citing paper
“the dKO mice, but not the single-knockout mice, show fewer acetylcholine receptor (AChR) clusters and a loss of apposition between AChR clusters and phrenic nerve terminals”
From The neurogenetics of alternative splicing (2016) · cites this paper as [73]
In the citing paper
“Nova1/2 dKO mice are born paralysed and die from respiratory failure indicative of NMJ defects73.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [73]
Citations
Cites
Directed differentiation of embryonic stem cells into motor neurons.
Wichterle, H., Lieberam, I., Porter, J. A., & Jessell, T. (2002) · Cell · doi:10.1016/s0092-8674(02)00835-8 · Cited by 1,792
HITS-CLIP yields genome-wide insights into brain alternative RNA processing
Licatalosi, D. D., Mele, A., Fak, J. J., Ule, J., Kayikci, M., Chi, S. W., Clark, T. A., Schweitzer, A. C., Blume, J. E., Wang, X., et al. (2008) · Nature · doi:10.1038/nature07488 · Cited by 1,352
Self-citationCLIP Identifies Nova-Regulated RNA Networks in the Brain
Ule, J., Jensen, K. B., Ruggiu, M., Mele, A., Ule, A., & Darnell, R. B. (2003) · Science · doi:10.1126/science.1090095 · Cited by 1,120
Self-citationParaneoplastic Syndromes Involving the Nervous System
Darnell, R. B., & Posner, J. B. (2003) · New England Journal of Medicine · doi:10.1056/nejmra023009 · Cited by 1,067
Self-citationDefective neuromuscular synaptogenesis in agrin-deficient mutant mice.
Gautam, M., Noakes, P., Moscoso, L. M., Rupp, F., Scheller, R., Merlie, J., & Sanes, J. (1996) · Cell · doi:10.1016/s0092-8674(00)81253-2 · Cited by 941
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 920
Self-citationLrp4 is a receptor for Agrin and forms a complex with MuSK
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. (2008) · Cell · doi:10.1016/j.cell.2008.10.002 · Cited by 676
Self-citationRequirement for the Homeobox Gene Hb9 in the Consolidation of Motor Neuron Identity
Arber, S., Han, B., Mendelsohn, M. M., Smith, M., Jessell, T. M., & Sockanathan, S. (1999) · Neuron · doi:10.1016/s0896-6273(01)80026-x · Cited by 607
Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse
Lin, W.-C., Burgess, R., Dominguez, B., Pfaff, S., Sanes, J., & Lee, K.-F. (2001) · Nature · doi:10.1038/35074025 · Cited by 560
Control of ACh sensitivity by muscle activity in the rat
Lømo, T., & Rosenthal, J. (1972) · The Journal of Physiology · doi:10.1113/jphysiol.1972.sp009764 · Cited by 533
An RNA map predicting Nova-dependent splicing regulation
Ule, J., Stefani, G., Mele, A., Ruggiu, M., Wang, X., Taneri, B., Gaasterland, T., Blencowe, B. J., & Darnell, R. B. (2006) · Nature · doi:10.1038/nature05304 · Cited by 528
Self-citationNova regulates brain-specific splicing to shape the synapse
Ule, J., Ule, A., Spencer, J., Williams, A., Hu, J.-S., Cline, M., Wang, H., Clark, T., Fraser, C., Ruggiu, M., et al. (2005) · Nature Genetics · doi:10.1038/ng1610 · Cited by 509
Self-citationPatterning of muscle acetylcholine receptor gene expression in the absence of motor innervation.
Yang, X., Arber, S., William, C., Li, L., Tanabe, Y., Jessell, T., Birchmeier, C., & Burden, S. (2001) · Neuron · doi:10.1016/s0896-6273(01)00287-2 · Cited by 504
Self-citationIdentification of agrin, a synaptic organizing protein from Torpedo electric organ.
Nitkin, R. M., Smith, M. A., Magill, C., Fallon, J. R., Yao, Y. M., Wallace, B. G., & McMahan, U. J. (1987) · The Journal of cell biology · doi:10.1083/jcb.105.6.2471 · Cited by 469
Nova-1 Regulates Neuron-Specific Alternative Splicing and Is Essential for Neuronal Viability
Jensen, K. B., Dredge, B. K., Stefani, G., Zhong, R., Buckanovich, R. J., Okano, H. J., Yang, Y. Y. L., & Darnell, R. B. (2000) · Neuron · doi:10.1016/s0896-6273(00)80900-9 · Cited by 426
Self-citationValenzuela, 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 418
Self-citationA study of foetal and new‐born rat muscle fibres
Diamond, J. M., & Miledi, R. (1962) · The Journal of Physiology · doi:10.1113/jphysiol.1962.sp006941 · Cited by 411
Specification of Motor Neuron Identity by the MNR2 Homeodomain Protein
Tanabe, Y., William, C. M., & Jessell, T. M. (1998) · Cell · doi:10.1016/s0092-8674(00)81783-3 · Cited by 341
Sequence-Specific RNA Binding by a Nova KH Domain
Lewis, H. A., Musunuru, K., Jensen, K. B., Edo, C., Chen, H., Darnell, R. B., & Burley, S. K. (2000) · Cell · doi:10.1016/s0092-8674(00)80668-6 · Cited by 326
Self-citationBuckanovich, R. J., Posner, J. B., & Darnell, R. B. (1993) · Neuron · doi:10.1016/0896-6273(93)90077-5 · Cited by 318
Self-citationOpposing effects of polyglutamine expansion on native protein complexes contribute to SCA1
Lim, J., Crespo-Barreto, J., Jafar-Nejad, P., Bowman, A. B., Richman, R., Hill, D. E., Orr, H. T., & Zoghbi, H. Y. (2008) · Nature · doi:10.1038/nature06731 · Cited by 311
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
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
Burgess, R., Nguyen, Q., Son, Y., Lichtman, J., & Sanes, J. (1999) · Neuron · doi:10.1016/s0896-6273(00)80751-5 · Cited by 257
The agrin gene codes for a family of basal lamina proteins that differ in function and distribution
Rüegg, M. A., Tsim, K. W. K., Horton, S. E., Kröger, S., Escher, G., Gensch, E. M., & McMahan, U. J. (1992) · Neuron · doi:10.1016/0896-6273(92)90090-z · Cited by 254
Godfrey, E. W., Nitkin, R. M., Wallace, B. G., Rubin, L. L., & McMahan, U. J. (1984) · The Journal of Cell Biology · doi:10.1083/jcb.99.2.615 · Cited by 251
Splicing Regulation in Neurologic Disease
Licatalosi, D. D., & Darnell, R. B. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.017 · Cited by 250
Self-citationAcetylcholine 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
Lin, W.-C., Dominguez, B., Yang, J.-F., Aryal, P., Brandon, E., Gage, F., & Lee, K.-F. (2005) · Neuron · doi:10.1016/j.neuron.2005.04.002 · Cited by 229
Agrin promotes synaptic differentiation by counteracting an inhibitory effect of neurotransmitter.
Misgeld, T., Kummer, T., Lichtman, J., & Sanes, J. (2005) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0504806102 · Cited by 223
Yang, Y. Y. L., Yin, G. L., & Darnell, R. B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.22.13254 · Cited by 219
Self-citationThe neuronal RNA binding protein Nova-1 recognizes specific RNA targets in vitro and in vivo
Buckanovich, R. J., & Darnell, R. B. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.6.3194 · Cited by 217
Self-citationFerns, M., Hoch, W., Campanelli, J. T., Rupp, F., Hall, Z. W., & Scheller, R. H. (1992) · Neuron · doi:10.1016/0896-6273(92)90129-2 · Cited by 212
Buckanovich, R., Yang, Y., & Darnell, R. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-03-01114.1996 · Cited by 192
Self-citationRNA binding proteins and the regulation of neuronal synaptic plasticity
Ule, J., & Darnell, R. B. (2006) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2006.01.003 · Cited by 181
Self-citationNerve-independent formation of a topologically complex postsynaptic apparatus
Kummer, T. T., Misgeld, T., Lichtman, J. W., & Sanes, J. R. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200401115 · Cited by 159
Huang, C. S., Shi, S.-H., Ule, J., Ruggiu, M., Barker, L. A., Darnell, R. B., Jan, Y. N., & Jan, L. Y. (2005) · Cell · doi:10.1016/j.cell.2005.07.033 · Cited by 157
Self-citationThe tetranucleotide UCAY directs the specific recognition of RNA by the Nova K-homology 3 domain
Jensen, K. B., Musunuru, K., Lewis, H. A., Burley, S. K., & Darnell, R. B. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.090553997 · Cited by 132
Self-citationDenzer, A. J., Gesemann, M., Schumacher, B., & Rüegg, M. A. (1995) · The Journal of Cell Biology · doi:10.1083/jcb.131.6.1547 · Cited by 129
Nova autoregulation reveals dual functions in neuronal splicing
Dredge, B. K., Stefani, G., Engelhard, C. C., & Darnell, R. B. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600630 · Cited by 125
Self-citationDredge, B. K., & Darnell, R. B. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.13.4687-4700.2003 · Cited by 120
Self-citationSynapse 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 117
Pun, S., Sigrist, M., Santos, A. F., Rüegg, M. A., Sanes, J. R., Jessell, T. M., Arber, S., & Caroni, P. (2002) · Neuron · doi:10.1016/s0896-6273(02)00670-0 · Cited by 117
Arber, S., Burden, S. J., & Harris, A. (2002) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(02)00296-9 · Cited by 58
Self-citationDeveloping Global Insight into RNA RegulationPreprint
Darnell, R. B. (2006) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2006.71.002 · Cited by 36
Self-citationEvidence for Muscle-Dependent Neuromuscular Synaptic Site Determination in Mammals
Vock, V. M., Ponomareva, O. N., & Rimer, M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5080-07.2008 · Cited by 31
Development of the neuromuscular synapse
Jennings, C. G. B., & Burden, S. J. (1993) · Current Opinion in Neurobiology · doi:10.1016/0959-4388(93)90038-z · Cited by 27
Self-citationMann, M. A., Das, S., Zhang, J., Wagner, M., & Fischbach, G. D. (2006) · Journal of Neurophysiology · doi:10.1152/jn.00225.2006 · Cited by 4
Self-citation
Cited by
Sorted by citations
Function of alternative splicing
Stamm, S., Ben‐Ari, S., Rafalska, I., Tang, Y., Zhang, Z., Toiber, D., Thanaraj, T. A., & Soreq, H. (2004) · Gene · doi:10.1016/j.gene.2004.10.022 · Cited by 1,398
RNA processing and its regulation: global insights into biological networks
Licatalosi, D. D., & Darnell, R. B. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2673 · Cited by 777
Self-citationFunction of alternative splicing
Kelemen, O., Convertini, P., Zhang, Z., Wen, Y., Shen, M., Falaleeva, M., & Stamm, S. (2013) · Gene · doi:10.1016/j.gene.2012.07.083 · Cited by 743
Functional consequences of developmentally regulated alternative splicing
Kalsotra, A., & Cooper, T. A. (2011) · Nature Reviews Genetics · doi:10.1038/nrg3052 · Cited by 729
To build a synapse: signaling pathways in neuromuscular junction assembly
Wu, H., Xiong, W., & Mei, L. (2010) · Development · doi:10.1242/dev.038711 · Cited by 534
Metadata
- Authors
- Ruggiu, M., Herbst, R., Kim, N., Jevsek, M., Fak, J. J., Mann, M. A., Fischbach, G., Burden, S. J., & Darnell, R. B.
- Affiliations
- Howard Hughes Medical Institute (US)
- NYU Langone Health (US)
- Molecular Neurobiology Program, Helen and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University Medical School, 540 First Avenue, New York, NY 10016; and
- Laboratory of Molecular Neuro-Oncology,
- Columbia University (US)
- Corresponding author
- Darnell, Robert B.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-03-03
- Volume
- 106
- Issue
- 9
- Pages
- 3513-3518
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2642475
- OpenAlex
- W2131636181
- Cited by
- 113
- References
- 48
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 8 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 9 · 2017: 8 · 2016: 10 · 2015: 7 · 2014: 6 · 2013: 9 · 2012: 7
- FWCI
- 3.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (R01 NS34389, NS34389)
- National Institute of Neurological Disorders and Stroke (R01NS040955, R01 NS34389, R01NS034389, NS40955, R01NS036193)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Clinical Neurology › Myasthenia Gravis and Thymoma
- Keywords
- NOVA1, NOVA2, alternative splicing, neuromuscular junction, synaptogenesis, acetylcholine receptor clustering, RNA regulation, synaptic transmission
- MeSH terms
- Neuro-Oncological Ventral Antigen, Amino Acid Sequence, Animals, Antigens, Neoplasm, Electrophysiology, Embryo, Mammalian, Gene Expression Regulation, Molecular Sequence Data, Nerve Tissue Proteins, Synapses, Motor Neuron Disease, RNA-Binding Proteins, Alternative Splicing, Agrin, Mice, Knockout, Protein Isoforms, Mice
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
