期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 9, 页码 3513-3518出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0813112106
关键词
alternative splicing; physiology; neuromuscular junction; neuron activity
资金
- Howard Hughes Medical Institute Funding Source: Medline
- NINDS NIH HHS [R01 NS036193, NS40955, R01 NS036193-12, R01 NS034389, R01 NS34389, R01 NS040955] Funding Source: Medline
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, neuronspecific 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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