Alpha Omega Alpha Honor Medical Society

2011 Research Abstract

Identification of negative regulators of SMN2 alternative splicing within the SR and hnRNP families

Investigators: Claribel D. Wee, Francine M. Jodelka, Mallory A. Havens, and Michelle L. Hastings, The Chicago Medical School at Rosalind Franklin University of Medicine and Science

Mentor: Michele L. Hastings, PhD, The Chicago Medical School at Rosalind Franklin University of Medicine and Science

Currently, there is no disease-modifying treatment available to patients with the inherited motor neuron disease spinal muscular atrophy (SMA). SMA is caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene and deficiency of SMN protein. Humans have a centromeric copy of the survival of motor neuron gene, SMN2, which predominantly encodes a truncated version of the SMN protein with reduced functionality. Thus, SMN2 cannot fully compensate for a loss of SMN1. The alternative splicing of SMN2 is orchestrated by the spliceosome, a complex of about 200 proteins in which the serine/arginine rich splicing factors (SRSF) and heterogeneous ribonucleoparticle (hnRNP) proteins are participants. In the current study we surveyed the SRSF and hnRNP families of proteins in the context of SMN2 exon 7 splicing. Knockdown of SRSF proteins using siRNA in HeLa showed a significant increase in the splicing of full length SMN2-derived transcripts concomitant with the independent knockdown of SRSF2, SRSF3, SRSF5, and SRSF11. Conversely, over-expression of these SRSF proteins in HeLa resulted in a significant decrease in the splicing of full length SMN2-derived transcripts. Similarly, independent knockdown of hnRNP A2B1, hnRNP C, and hnRNP U resulted in significant increase in the splicing of full length SMN2-derived transcripts. Independent knockdown of SRSF3 and SRSF11 in two cell lines derived from severe SMA patients increased the splicing of full-length SMN2-derived transcripts as well as SMN protein. These results suggest that the aforementioned members of the SRSF family of proteins are negative regulators of SMN2 exon 7 splicing. As such, these SRSF proteins are potentially promising therapeutic targets in the treatment of SMA patients.

Updated on July 31, 2012.


© 2017 Alpha Omega Alpha Honor Medical Society