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.
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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
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
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