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Shafey D, MacKenzie AE, Kothary R: Neurodevelopmental abnormalities in neurosphere-derived neural stem cells from SMN-depleted mice. J Neurosci Res. 2008 Oct;86(13):2839-47.
Spinal muscular atrophy (SMA) is a genetic disorder caused by depletion of survival motor neuron (SMN) protein and characterized by degeneration of alpha-motor neurons in the spinal cord. We 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 the number of Tuj1-positive cells was not a result of enhanced apoptosis but was accompanied by an increase in the number of nestin-positive cells. These results provide 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 affects neurodevelopment and neuromaintenance to varying extents, leading to SMA pathogenesis. |
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