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
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Self-citationCLIP Identifies Nova-Regulated RNA Networks in the Brain
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Self-citationParaneoplastic Syndromes Involving the Nervous System
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Self-citationDefective neuromuscular synaptogenesis in agrin-deficient mutant mice.
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Self-citationLrp4 is a receptor for Agrin and forms a complex with MuSK
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Items 101–113 of 113
Neuron-specific cTag-CLIP reveals cell-specific diversity of functional RNA regulation in the brainPreprint
Saito, Y., Yuan, Y., Zucker-Scharff, I., Fak, J. J., Tajima, Y., Licatalosi, D. D., & Darnell, R. B. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/244905 · Cited by 2
Self-citationOncogenic NOVA1 expression dysregulates alternative splicing in breast cancerPreprint
Moakley, D. F., & Zhang, C. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.08.602566 · Cited by 2
Hossain, M. F., Popsuj, S., Vitrinel, B., Kaplan, N., Stolfi, A., Christiaen, L., & Ruggiu, M. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3003392 · Cited by 1
Self-citationCastro, A. F., Figueiredo, A. S., Loureiro, J. R., Azevedo, M. M., Sampaio, P., Valentim, A. M., Bessa, J., & Silveira, I. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.26.672304 · Cited by 1
Recent Advances in Understanding of Alternative Splicing in Neuronal Pathogenesis
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Functional impact of alternative splicing in vertebrate proteomes across tissues and cell types
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Essential Role of nSR100 and CPEB4 Proteins During the Development of the Nervous System
Venkata, S. G., & Rajagopal, S. (2022) · Nutritional neurosciences · doi:10.1007/978-981-15-9781-7_13
Advances in Physiological Outcomes of Alternative Splicing Transitions
Singh, N., Puri, B., & Gupta, D. K. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-821618-7.00205-4
Regulation of glioblastoma proliferation and migration by Nova1Preprint
Yao, X., Wang, B., Su, Y., Wang, N., Dong, Q., Yin, H., Qiu, G., Wang, X., Pan, Y., & Yuan, G. (2023) · Research Square · doi:10.21203/rs.3.rs-2660025/v1
A conserved RNA switch for acetylcholine receptor clustering at neuromuscular junctions in chordatesPreprint
Hossain, M. F., Popsuj, S., Vitrinel, B., Kaplan, N., Stolfi, A., Christiaen, L., & Ruggiu, M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.05.602308
Self-citationThe role of serotoninergic neurons in amyotrophic lateral sclerosis
Oussini, H. E. (2016) · theses.fr (ABES) · doi:10.70675/2431e8ddzd4e4z4710z81dcz14100daa6294
Conditional truncation of the FUS protein in mice : a new animal model of the ALS/FTD continuum
Scekic‐Zahirovic, J. (2016) · theses.fr (ABES) · doi:10.70675/6bed4f95z0a05z438fz937ez33f29f11923d
Mécanismes moléculaires à l'origine de la dysautonomie familiale
Hervé, M. (2016) · theses.fr (ABES) · doi:10.70675/6564ee49z2810z4387zb80azee2206033835
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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