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Molecular and Cellular Biology, July 2003, p. 4687-4700, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4687-4700.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Nova Regulates GABAA Receptor {gamma}2 Alternative Splicing via a Distal Downstream UCAU-Rich Intronic Splicing Enhancer

B. Kate Dredge and Robert B. Darnell*

Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021

Received 7 March 2003/ Accepted 14 April 2003

Nova is a neuron-specific RNA binding protein targeted in patients with the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia, which is characterized by failure of inhibition of brainstem and spinal motor systems. Here, we have biochemically confirmed the observation that splicing regulation of the inhibitory GABAA receptor {gamma}2 (GABAAR{gamma}2) subunit pre-mRNA exon E9 is disrupted in mice lacking Nova-1. To elucidate the mechanism by which Nova-1 regulates GABAAR{gamma}2 alternative splicing, we systematically screened minigenes derived from the GABAAR{gamma}2 and human ß-globin genes for their ability to support Nova-dependent splicing in transient transfection assays. These studies demonstrate that Nova-1 acts directly on GABAAR{gamma}2 pre-mRNA to regulate E9 splicing and identify an intronic region that is necessary and sufficient for Nova-dependent enhancement of exon inclusion, which we term the NISE (Nova-dependent intronic splicing enhancer) element. The NISE element (located 80 nucleotides upstream of the splice acceptor site of the downstream exon E10) is composed of repeats of the sequence YCAY, consistent with previous studies of the mechanism by which Nova binds RNA. Mutation of these repeats abolishes binding of Nova-1 to the RNA in vitro and Nova-dependent splicing regulation in vivo. These data provide a molecular basis for understanding Nova regulation of GABAAR{gamma}2 alternative splicing and suggest that general dysregulation of Nova's splicing enhancer function may underlie the neurologic defects seen in Nova's absence.

* Corresponding author. Mailing address: Laboratory of Molecular Neuro-Oncology, The Rockefeller University, 1230 York Ave., Box 226, New York, NY 10021. Phone: (212) 327-7460. Fax: (212) 327-7109. E-mail: darnelr{at}rockefeller.edu.

Molecular and Cellular Biology, July 2003, p. 4687-4700, Vol. 23, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.13.4687-4700.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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