title: Activation of RNA metabolism-related genes in mouse but not human tissues deficient in SMN.
abstract: Mutations of the survival of motor neuron gene (SMN1) are responsible for spinal muscular atrophies (SMA), a frequent recessive autosomal motor neuron disease. SMN is involved in various processes including RNA metabolism. However, the molecular pathway linking marked deficiency of SMN to SMA phenotype remains unclear. Homozygous deletion of murine Smn exon 7 directed to neurons or skeletal muscle causes severe motor axonal or myofiber degeneration, respectively. With the use of cDNA microarrays, expression profiles of 8,400 genes were analyzed in skeletal muscle and spinal cord of muscular and neuronal mutants, respectively, and compared with age-matched controls. A high proportion of genes (20 of 429, 5%) was involved in pre-mRNA splicing, ribosomal RNA processing, or RNA decay, and 18 of them were upregulated in mutant tissues. By analyzing other neuromuscular disorders, we showed that most of them (14 of 18) were specific to the SMN defect. Quantitative PCR analysis of these transcripts showed that gene activation was an early adaptive response to the lack but not reduced amount of full-length SMN in mouse mutant tissues. In human SMA tissues, activation of this program was not observed, which could be ascribed to the reduction but not the absence of full-length SMN.
authors.affiliation: Molecular Neurogenetics Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM), E-223, University of Evry, Genopole, Evry, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Olaso
authors.forename: Vandana
authors.initials: V
authors.lastname: Joshi
authors.forename: Julien
authors.initials: J
authors.lastname: Fernandez
authors.forename: Natacha
authors.initials: N
authors.lastname: Roblot
authors.forename: Sabrina
authors.initials: S
authors.lastname: Courageot
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Bonnefont
authors.forename: Judith
authors.initials: J
authors.lastname: Melki
mesh_terms: D000818:Animals; D015415:Biomarkers; D016022:Case-Control Studies; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005333:Fetus / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009134:Muscular Atrophy, Spinal / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D015533:Transcriptional Activation
chemical_list: D015415:Biomarkers; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D012313:RNA