SMN Deficiency Causes Tissue-Specific Perturbations in the Repertoire of snRNAs and Widespread Defects in Splicing

Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6148, USA.
Cell (Impact Factor: 32.24). 06/2008; 133(4):585-600. DOI: 10.1016/j.cell.2008.03.031
Source: PubMed


The survival of motor neurons (SMN) protein is essential for the biogenesis of small nuclear RNA (snRNA)-ribonucleoproteins (snRNPs), the major components of the pre-mRNA splicing machinery. Though it is ubiquitously expressed, SMN deficiency causes the motor neuron degenerative disease spinal muscular atrophy (SMA). We show here that SMN deficiency, similar to that which occurs in severe SMA, has unexpected cell type-specific effects on the repertoire of snRNAs and mRNAs. It alters the stoichiometry of snRNAs and causes widespread pre-mRNA splicing defects in numerous transcripts of diverse genes, preferentially those containing a large number of introns, in SMN-deficient mouse tissues. These findings reveal a key role for the SMN complex in RNA metabolism and in splicing regulation and indicate that SMA is a general splicing disease that is not restricted to motor neurons.

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    • "of research, the specific sensitivity of motor neurons to defects of the ubiquitous SMN protein that is involved in essential cell processes such as mRNA metabolism (Fischer et al., 1997; Pellizzoni et al., 1998) remains poorly understood. Microarray analyses unexpectedly failed to identify the specific misexpression of some essential genes in motor neurons after SMN depletion (Zhang et al., 2008). This may suggest that the selective degeneration of motor neurons in SMA results from alterations of systemic pathways that would ultimately target motor neurons. "
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    ABSTRACT: Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by the selective loss of spinal motor neurons due to the depletion of the survival of motor neuron (SMN) protein. No therapy is currently available for SMA, which represents the leading genetic cause of death in childhood. In the present study, we report that insulin-like growth factor-1 receptor (Igf-1r) gene expression is enhanced in the spinal cords of SMA-like mice. The reduction of expression, either at the physiological (through physical exercise) or genetic level, resulted in the following: (1) a significant improvement in lifespan and motor behavior, (2) a significant motor neuron protection, and (3) an increase in SMN expression in spinal cord and skeletal muscles through both transcriptional and posttranscriptional mechanisms. Furthermore, we have found that reducing IGF-1R expression is sufficient to restore intracellular signaling pathway activation profile lying downstream of IGF-1R, resulting in both the powerful activation of the neuroprotective AKT/CREB pathway and the inhibition of the ERK and JAK pathways. Therefore, reducing rather than enhancing the IGF-1 pathway could constitute a useful strategy to limit neurodegeneration in SMA.
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    • "In complex with specific proteins, Gemins2-8 and unrip, SMN mediates the formation of the seven-membered Sm core domain of uridinerich spliceosomal snRNPs (Fischer et al. 1997; Liu et al. 1997; Chari et al. 2008). Indeed, alterations in the snRNP repertoire as a consequence of reduced Smn levels have already been reported (Gabanella et al. 2007; Zhang et al. 2008) and there is also evidence that such alterations contribute to altered pre-mRNA splicing over time (Zhang et al. 2008; Lotti et al. 2012). However, to what extent such splicing defects are directly caused by Smn loss or are secondary effects as a response to cellular dysfunction remains to be determined (Baumer et al. 2009; Garcia et al. 2013). "
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