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Human Molecular Genetics, 2002, Vol. 11, No. 5 577-587
© 2002 Oxford University Press

SRp30c-dependent stimulation of survival motor neuron (SMN) exon 7 inclusion is facilitated by a direct interaction with hTra2ß1

Philip J. Young, Christine J. DiDonato1, Diane Hu, Rashmi Kothary1, Elliot J. Androphy2 and Christian L. Lorson+

Arizona State University, Department of Biology, Tempe, AZ 85287-1501, USA, 1Ottawa Health Research Institute, Ottawa, Ontario K1H 8L6, Canada and 2Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA

Proximal spinal muscular atrophy (SMA) is caused by the homozygous loss of survival motor neuron (SMN1). SMN2, a nearly identical copy gene, is present in all SMA patients; however this gene cannot provide protection from disease due to the aberrant splicing of a critical exon. SMN1-derived transcripts are exclusively full-length, whereas SMN2-derived transcripts predominantly lack SMN exon 7. A single non-polymorphic nucleotide difference (C in SMN1; T in SMN2) is responsible for the alternative splicing patterns. We have previously shown that transient expression of an SR-like splicing factor, hTra2ß1, stimulates inclusion of exon 7 in SMN2-derived mini-gene transcripts through an interaction with the AG-rich exonic splice enhancer within exon 7. We now demonstrate that a second splicing factor, SRp30c, can stimulate SMN exon 7-inclusion and that this activity required the same AG-rich enhancer as hTra2ß1. SRp30c did not directly associate with SMN exon 7; rather its association with the exonic enhancer was mediated by a direct interaction with hTra2ß1. In the absence of the hTra2ß1 binding site, SRp30c failed to complex with SMN exon 7. Taken together, these results identify SRp30c as a modulator of SMN exon 7-inclusion and provide insight into the molecular regulation of this critical exon.

+ To whom correspondence should be addressed. Tel: +1 480 965 5444; Fax: +1 480 965 2519; Email: clorson@asu.edu


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