Résumé :
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Spinal muscular atrophy (SMA) is the most common genetic disease resulting in infant mortality. SMA manifests itself due to a severe loss of ?-motor neurons and is caused by mutations or deletions of the ubiquitously expressed survival motor neuron 1 (SMN1) gene. However, why ?-motor neurons of SMA patients are specifically affected is not clear. We have previously demonstrated that Smn-deficient PC12 cells show altered Profilin II expression and an upregulation of the RhoA/ROCK pathway accompanying defects in neuronal integrity. Here, we have investigated the morphology and differentiation of neurosphere-derived neural stem cells (NSCs) generated from the brains of a hypomorphic series of SMA mice. Neurospheres from the Smn-/-;SMN2 mice, which represent a model of very severe SMA, produced NSCs with increased proliferation during growth and differentiation. These cells produced fewer Tuj1-positive neuronal cells, which displayed morphological alterations and had fewer and shorter neurites. The decrease in Tuj1-positive cells was not due to enhanced apoptosis but was accompanied by an increase in the number of nestin-positive cells. These results give us insight into the most severe model of SMA in which SMN is nearly completely depleted, and suggest that SMN has a role in neurodevelopment as well as in neuromaintenance. Our work raises the possibility that SMN depletion impacts neurodevelopment and neuromaintenance to varying extents leading to SMA pathogenesis. We are currently investigating the impact of Smn depletion on embryonic development using the Smn-/-;SMN2 mouse as a model.
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