Résumé :
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Spinal muscular atrophy (SMA) is amongst the leading genetic causes of infant deaths and is characterized by specific degeneration and loss of spinal cord motoneurons. It is caused by the disruption of the "survival of motor neurons" gene (Smn1), which plays an essential role in the cytoplasmic assembly of core snRNPs. Beyond its well-characterized role in snRNP assembly, and the fact that this process should be equally important to all cells,the molecular defect(s) leading to motoneuron-specific pathologies and development of SMA remains unknown. Consequently, there ought to be more focus on the other functions of SMN. For example, it was suggested that the nuclear pool of SMN might play a more direct role in pre-mRNA splicing and/or transcription. Indeed, a methyl-dependent interaction between the SMN Tudor domain and CA150, a protein thought to be involved in bridging transcription and splicing was previously reported. Alternatively, SMN was found to localize to RNA-containing foci in axons, where it functionally interacts with methylated RNA binding proteins such as KHSRP and HuD. Thus, in order to investigate these other functions, we developed a stable motoneuron MN-1 cell line expressing a shRNA against SMN. Interestingly, an increase of the CARM1 protein level was observed in these -SMN cells. Remarkably, this increase in CARM1 was also observed by western blot experiments on spinal cord lysates from E14 SMA mice. CARM1 is a known regulator of SMN interactions and is emerging as a master regulator of the proliferative/differentiation switch for a number of cell lineages, including motoneurons. Hence, this observation may provide crucial insights into our understanding of the etiology of SMA. Furthermore, our experiments have shown that SMN in fact regulates expression of CARM1 (and a number of other proteins) at the level of translation. This constitutes a novel function for SMN and reveals the importance of quantitative proteomic studies in the analysis of SMA patient samples and animal models. Altogether, a better understanding of the distinct roles of SMN and the consequences of losing these functions will be crucial for a complete understanding of the pathology.
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