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Molecular and Cellular Biology, February 2008, p. 1240-1251, Vol. 28, No. 4
0270-7306/08/$08.00+0     doi:10.1128/MCB.01509-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of Neuron-Specific Alternative Splicing of Neurofibromatosis Type 1 Pre-mRNA{triangledown}

Hui Zhu,1,{dagger} Melissa N. Hinman,1 Robert A. Hasman,1 Priyesh Mehta,1 and Hua Lou1,2,3*

Department of Genetics,1 Center for RNA Molecular Biology,2 Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio 441063

Received 20 August 2007/ Returned for modification 4 September 2007/ Accepted 27 November 2007

Neurofibromatosis type 1 (NF1) is one of the most common heritable autosomal dominant disorders. Alternative splicing modulates the function of neurofibromin, the NF1 gene product, by inserting the in-frame exon 23a into the region of NF1 mRNA that encodes the GTPase-activating protein-related domain. This insertion, which is predominantly skipped in neurons, reduces the ability of neurofibromin to regulate Ras by 10-fold. Here, we report that the neuron-specific Hu proteins control the production of the short protein isoform by suppressing inclusion of NF1 exon 23a, while TIA-1/TIAR proteins promote inclusion of this exon. We identify two binding sites for Hu proteins, located upstream and downstream of the regulated exon, and provide biochemical evidence that Hu proteins specifically block exon definition by preventing binding of essential splicing factors. In vitro analyses using nuclear extracts show that at the downstream site, Hu proteins prevent binding of U1 and U6 snRNPs to the 5' splice site, while TIAR increases binding. Hu proteins also decrease U2AF binding at the 3' splice site located upstream of exon 23a. In addition to providing the first mechanistic insight into tissue-specific control of NF1 splicing, these studies establish a novel strategy whereby Hu proteins regulate RNA processing.

* Corresponding author. Mailing address: Department of Genetics, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. Phone: (216) 368-6419. Fax: (216) 368-0491. E-mail: hxl47{at}case.edu

{triangledown} Published ahead of print on 17 December 2007.

{dagger} Present address: Genomic Medicine Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195.

Molecular and Cellular Biology, February 2008, p. 1240-1251, Vol. 28, No. 4
0270-7306/08/$08.00+0     doi:10.1128/MCB.01509-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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