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Molecular and Cellular Biology, November 2008, p. 6929-6938, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.01332-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The RNA Binding Protein hnRNP Q Modulates the Utilization of Exon 7 in the Survival Motor Neuron 2 (SMN2) Gene{triangledown} ,{dagger}

Hung-Hsi Chen,1 Jan-Growth Chang,2 Ruei-Min Lu,1 Tsui-Yi Peng,1,3 and Woan-Yuh Tarn1*

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan,1 Department of Medical Research, Kaohsiung Medical University Hospital and Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan,2 Institute of Molecular Medicine, National Tsing Hua University, Hsin-Chu, Taiwan3

Received 20 August 2008/ Accepted 3 September 2008

Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by the homozygous loss of the SMN1 gene. The human SMN2 gene has a C-to-T transition at position +6 of exon 7 and thus produces exon 7-skipping mRNAs. However, we observed an unexpectedly high level of exon 7-containing SMN2 transcripts as well as SMN protein in testis of smn–/– SMN2 transgenic mice. Using affinity chromatography, we identified several SMN RNA-associating proteins in mouse testis and human HeLa cells, including hnRNP Q. The major hnRNP Q isoform, Q1, directly bound SMN exon 7 in the vicinity of nucleotide +6. Overexpression of hnRNP Q1 promoted the inclusion of exon 7 in SMN2, probably by activating the use of its upstream 3' splice site. However, the minor isoforms Q2/Q3 could antagonize the activity of hnRNP Q1 and induced exon 7 exclusion. Intriguingly, enhanced exon 7 inclusion was also observed upon concomitant depletion of three hnRNP Q isoforms. Thus, differential expression of hnRNP Q isoforms may result in intricate control of SMN precursor mRNA splicing. Here, we demonstrate that hnRNP Q is a splicing modulator of SMN, further underscoring the potential of hnRNP Q as a therapeutic target for SMA.

* Corresponding author. Mailing address: Institute of Biomedical Sciences, Academia Sinica, 128 Academy Road Section 2, Nankang, Taipei 11529, Taiwan. Phone: 8862 2652 3052. Fax: 8862 2782 9142. E-mail: wtarn{at}ibms.sinica.edu.tw

{triangledown} Published ahead of print on 15 September 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2008, p. 6929-6938, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.01332-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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