Résumé :
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Communication n° 266 Spinal Muscular Atrophy (SMA) is a frequent autosomal recessive disorder characterized by degeneration of motor neurons (MN) in the spinal cord and caused by mutations of the SMN1 gene. SMN is involved in RNA metabolism. Mouse model carrying homozygous deletion of Smn exon 7 directed to neurons has been generated. Mutant mice display a dramatic loss of motor axons (73%) contrasting with moderate loss of MN cell bodies (30%). Moreover, they revealed a lack of axonal sprouting and abnormal accumulation of neurofilaments at the motor endplate (Frugier et al., 2000, Cifuentes-Diaz et al., 2002). SMA models in other organisms have revealed defects of motor axon development or maintenance. Finally, recent in vitro experiments have shown that SMN localizes with cytoskeletal filaments and is actively transported in axons, suggesting that SMN might be involved in axonal transport of RNA-protein complexes (Zhang et al., Rossoll et al, 2003). In order to refine SMN and SMNdeltaexon7 localization in motor axons and to evaluate the putative axonal transport of SMN in vivo, we are generating transgenic mice carrying GFP-SMN or GFP-SMNdeltaexon7. In parallel, immunoprecipitation experiments of SMN or GFP-SMN proteins should allow the identification of SMN partners in neural system. Furthermore, to clarify the role of SMN in axonal transport, sciatic nerve ligation experiments followed by the analysis of both transported proteins and proteins involved in axonal transport have been undertaken in SMN mutant mice. Preliminary results suggest a defect of axonal transport in 30 day-old mutant mice. Further analysis of non-affected younger mutant mice will permit to known whether this defect is primary or secondary to the axonal degeneration. In addition, we are currently determining whether this defect is restricted to a specific type of axonal transport. These approaches should clarify the link between RNA metabolism, motor axon maintenance and axonal transport.
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