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. Using cDNA microarrays, expression profiles of 8400 genes were analyzed in skeletal muscle and spinal cord of muscular and neuronal mutants, respectively and compared to age-matched controls. A high proportion of genes (20 out 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 analysing other neuromuscular disorders, we showed that most of them (14 out 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.