title: Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells.
abstract: Spinal muscular atrophy (SMA) is a recessive disorder involving the loss of motor neurons from the spinal cord. Homozygous absence of the survival of motor neuron 1 gene (SMN1) is the main cause of SMA, but disease severity depends primarily on the number of SMN2 gene copies. SMN protein levels are high in normal spinal cord and much lower in the spinal cord of SMA patients, suggesting neuron-specific regulation for this ubiquitously expressed gene. We isolated genomic DNA from individuals with SMN1 or SMN2 deletions and sequenced 4.6 kb of the 5' upstream regions of the these. We found that these upstream regions, one of which is telomeric and the other centromeric, were identical. We investigated the early regulation of SMN expression by transiently transfecting mouse embryonic spinal cord and fibroblast primary cultures with three transgenes containing 1.8, 3.2 and 4.6, respectively, of the SMN promoter driving beta-galactosidase gene expression. The 4.6 kb construct gave reporter gene expression levels five times higher in neurons than in fibroblasts, due to the combined effects of a general enhancer and a non-neuronal cell silencer. The differential expression observed in neurons and fibroblasts suggests that the SMN genes play a neuron-specific role during development. An understanding of the mechanisms regulating SMN promoter activity may provide new avenues for the treatment of SMA.
authors.affiliation: Neurogénétique/INSERM E9935, Hôpital Robert Debré, 48 Boulevard Sérurier, Paris, France.
authors.forename: Bernadett
authors.initials: B
authors.lastname: Boda
authors.forename: Christophe
authors.initials: C
authors.lastname: Mas
authors.forename: Catherine
authors.initials: C
authors.lastname: Giudicelli
authors.forename: Virginie
authors.initials: V
authors.lastname: Nepote
authors.forename: Fabien
authors.initials: F
authors.lastname: Guimiot
authors.forename: Béatrice
authors.initials: B
authors.lastname: Levacher
authors.forename: Agnes
authors.initials: A
authors.lastname: Zvara
authors.forename: Miklos
authors.initials: M
authors.lastname: Santha
authors.forename: Isabelle
authors.initials: I
authors.lastname: LeGall
authors.forename: Michel
authors.initials: M
authors.lastname: Simonneau
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D040461:Gene Components; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D017422:Sequence Analysis, DNA; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D014162:Transfection; D019076:Transgenes / Q000235:genetics
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein