Rescuing Z+ agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing.

Full 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.

Author information

Author/s: Ruggiu, Matteo (M); Herbst, Ruth (R); Kim, Natalie (N); Jevsek, Marko (M); Fak, John J (JJ); Mann, Mary Anne (MA); Fischbach, Gerald (G); Burden, Steven J (SJ); Darnell, Robert B (RB);

Affiliation: Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

Grants: NS40955 (Agency:NINDS NIH HHS) ; R01 NS34389 (Agency:NINDS NIH HHS) ; (Agency:Howard Hughes Medical Institute)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A), published in United States. (Language: eng)

Reference: 2009-Mar; vol 106 (issue 9) : pp 3513-8

Dates: Created 2009/03/04; Completed 2009/04/01;

PMID: 19221030, status: MEDLINE (last retrieval date: 4/1/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Agrin - chemistry; genetics; metabolism
Alternative Splicing - genetics
Amino Acid Sequence
Animals
Antigens, Neoplasm - genetics; metabolism
Electrophysiology
Embryo, Mammalian - embryology; metabolism
Gene Expression Regulation

Mice
Mice, Knockout
Molecular Sequence Data
Motor Neuron Disease - genetics; metabolism; physiopathology
Nerve Tissue Proteins - deficiency; genetics; metabolism
Protein Isoforms - chemistry; genetics; metabolism
RNA-Binding Proteins - genetics; metabolism
Synapses - metabolism

Associated Chemicals: Agrin (0) ; Antigens, Neoplasm (0) ; Nerve Tissue Proteins (0) ; Nova antigen (0) ; Protein Isoforms (0) ; RNA-Binding Proteins (0)

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