Rescuing Z + agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing
| Autor: | Robert B. Darnell, John J. Fak, Ruth Herbst, Mary Anne Mann, Natalie Kim, Steven J. Burden, Matteo Ruggiu, Gerald D. Fischbach, Marko Jevsek |
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| Rok vydání: | 2009 |
| Předmět: |
animal structures
Molecular Sequence Data Nerve Tissue Proteins Neurotransmission Biology Neuromuscular junction Synapse Mice Antigens Neoplasm Neuro-Oncological Ventral Antigen medicine Animals Protein Isoforms Agrin Amino Acid Sequence Motor Neuron Disease Axon Acetylcholine receptor Mice Knockout Multidisciplinary RNA-Binding Proteins Biological Sciences Motor neuron Embryo Mammalian Cell biology Electrophysiology Alternative Splicing medicine.anatomical_structure Gene Expression Regulation nervous system Synapses Immunology medicine.symptom Muscle contraction |
| Zdroj: | Proceedings of the National Academy of Sciences. 106:3513-3518 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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