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Spinal muscular atrophy - Yunlong Liu Lab

SMN depletion results in splicing defects in a neuronal cell model of spinal muscular atrophy


Sara K. Custer*, Timra D. Gilson*, Hongxia Li, A. Gary Todd, Hai Lin, Yunlong Liu, and Elliot J. Androphy


Abstract


Spinal muscular atrophy (SMA) is an intractable neurodegenerative disease afflicting 1 in 10,000 live births. One of the key functions of the SMN protein is regulation of spliceosome assembly. Reduced levels of the SMN protein that are observed in SMA have been shown to result in aberrant mRNA splicing. SMN-dependent mis-spliced transcripts in motor neurons may cause stresses that are particularly harmful and may serve as potential targets for the treatment of motor neuron disease or as biomarkers in the SMA patient population. We performed RNA sequencing using a motor neuron-like NSC-34 cell model of SMA to screen for SMN-dependent mRNA processing changes that occur following acute depletion of SMN. We identified SMN-dependent splicing changes, including an intron retention event that results in the production of a truncated Rit1 transcript. Constitutively active Rit1 ameliorated the neurite outgrowth defect in SMN depleted NSC-34 cells, while expression of the truncated protein product of the mis-spliced Rit1 transcript inhibited neurite extension. These results reveal new insights into the biological consequence of SMN-dependent splicing in a cell culture model of spinal muscular atrophy.
 
The bam file of the RNA-seq data can be downloaded from the following links:

COPa IP RNA SMN WT
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COPa IP RNA SMN KD
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Total pool RNA SMN WT
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Total pool RNA SMN KD
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