Title

Temporal Requirement for High SMN Expression in SMA Mice

Document Type

Article

Publication Date

9-15-2011

Abstract

Spinal muscular atrophy (SMA) is caused by loss of the survival motor neuron 1 gene (SMN1) and retention of the SMN2 gene, resulting in reduced SMN. SMA mice can be rescued with high expression of SMN in neurons, but when is this high expression required? We have developed a SMA mouse with inducible expression of SMN to address the temporal requirement for high SMN expression. Both embryonic and early postnatal induction of SMN resulted in a dramatic increase in survival with some mice living greater than 200 days. The mice had no marked motor deficits and neuromuscular junction (NMJ) function was near normal thus it appears that induction of SMN in postnatal SMA mice rescues motor function. Early postnatal SMN induction, followed by a 1-month removal of induction at 28 days of age, resulted in no morphological or electrophysiological abnormalities at the NMJ and no overt motor phenotype. Upon removal of SMN induction, five mice survived for just over 1 month and two female mice have survived past 8 months of age. We suggest that there is a postnatal period of time when high SMN levels are required. Furthermore, two copies of SMN2 provide the minimal amount of SMN necessary to maintain survival during adulthood. Finally, in the course of SMA, early induction of SMN is most efficacious.

DOI

10.1093/hmg/ddr275