Neurodevelopmental abnormalities in neurosphere-derived neural stem cells from SMN-depleted mice.
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.
Ottawa Health Research Institute, Ottawa, Ontario, Canada.
Dina
D
Shafey
Alex E
AE
MacKenzie
Rashmi
R
Kothary
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*
C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein