Human Molecular Genetics Advance Access originally published online on January 4, 2008
Human Molecular Genetics 2008 17(8):1063-1075; doi:10.1093/hmg/ddm379
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Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect
1 Department of Molecular and Cellular Biochemistry 2 Department of Neurology 3 Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA 4 Department of Neurology 5 Department of Pediatrics, Johns Hopkins Hospital, Baltimore, MD 21287, USA 6 Feinberg School of Medicine, Department of Pediatrics, Northwestern University and Children’s Memorial Research Center, Chicago, IL 60614, USA 7 Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY 10027, USA 8 Wolfson Centre for Inherited Neuromuscular Disease, Leopold Muller ARC Building, RJAH Orthopaedic Hospital, Oswestry, Shropshire SY10 7AG, UK 9 Institute of Science and Technology in Medicine, Keele University, Stoke-on-Trent ST4 7QB, UK
* To whom correspondence should be addressed at: Department of Molecular and Cellular Biochemistry, The Ohio State University, 363 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA. Tel: +1 6146884759; Fax: +1 6142924118; Email: burghes.1{at}osu.edu
Received October 12, 2007; Accepted December 20, 2007
Spinal muscular atrophy (SMA) is caused by loss of the survival motor neuron gene (SMN1) and retention of the SMN2 gene. The copy number of SMN2 affects the amount of SMN protein produced and the severity of the SMA phenotype. While loss of mouse Smn is embryonic lethal, two copies of SMN2 prevents this embryonic lethality resulting in a mouse with severe SMA that dies 5 days after birth. Here we show that expression of full-length SMN under the prion promoter (PrP) rescues severe SMA mice. The PrP results in high levels of SMN in neurons at embryonic day 15. Mice homozygous for PrP-SMN with two copies of SMN2 and lacking mouse Smn survive for an average of 210 days and lumbar motor neuron root counts in these mice were normal. Expression of SMN solely in skeletal muscle using the human skeletal actin (HSA) promoter resulted in no improvement of the SMA phenotype or extension of survival. One HSA line displaying nerve expression of SMN did affect the SMA phenotype with mice living for an average of 160 days. Thus, we conclude that expression of full-length SMN in neurons can correct the severe SMA phenotype in mice. Furthermore, a small increase of SMN in neurons has a substantial impact on survival of SMA mice while high SMN levels in mature skeletal muscle alone has no impact.
The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Authors.
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