Author/Editor		Ruggiu, Matteo; Herbst, Ruth; Kim, Natalie; Jevšek, Marko; Fak, John J; Mann, Mary Ann; Fischbach, Gerald; Burden, Steven J; Darnell, Robert B
Title		Rescuing Z+ agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing
Type		članek
Source		Proc Natl Acad Sci U S A
Vol. and No.		Letnik 106, št. 9
Publication year		2009
Volume		str. 3513-8
Language		eng
Abstract		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.
Descriptors		AGRIN ALTERNATIVE SPLICING AMINO ACID SEQUENCE ANIMALS ANTIGENS, NEOPLASM ELECTROPHYSIOLOGY GENE EXPRESSION REGULATION MICE MICE, KNOCKOUT MOLECULAR SEQUENCE DATA MOTOR NEURON DISEASE NERVE TISSUE PROTEINS RNA-BINDING PROTEINS SYNAPSES