Human Molecular Genetics Advance Access published online on January 4, 2008
Human Molecular Genetics, 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, The Ohio State University, Columbus, OH, 43210 USA 2 Department of Neurology, The Ohio State University, Columbus, OH, 43210 USA 3 Departments of Neurology and Pediatrics, Johns Hopkins University, Baltimore, MD, 21287 USA 4 Department of Pediatrics, Feinberg School of Medicine, Northwestern University and Children's Memorial Research Center, Chicago, IL, 60614 5 Department of Neurology, College of Physicians and Surgeons Columbia University, New York, NY, 10027 USA Wolfson 6 Centre for Inherited Neuromuscular Disease, Leopold Muller ARC Building, RJAH Orthopaedic Hospital, Oswestry, Shropshire SY10 7AG, UK and Institute of Science and Technology in Medicine, Keele University, ST4 7QB, UK 7 Department of Molecular Genetics, Ohio State University, Columbus, OH, 43210 USA
* To whom correspondence should be addressed: Arthur Burghes, Department of Molecular and Cellular Biochemistry, 363 Hamilton Hall, 1645 Neil Ave., Columbus, OH, 43210 USA. Tel +1 6146884759; Fax: +1 6142924118 Email: Burghes.1{at}osu.edu
Received October 12, 2007; Revised December 20, 2007; Accepted December 20, 2007
Spinal muscular atrophy is caused by loss of the SMN1 gene 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 prion promoter 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.
These authors contribute equally to the manuscript
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