Abstract
Spinal muscular atrophy (SMA) is a severe motor neuron degenerative disease caused by loss-of-function mutations in the survival motor neuron gene SMN1. It is widely posited that defective gene expression underlies SMA. However, the identities of these affected genes remain to be elucidated. By analyzing the transcriptome of a Caenorhabditis elegans SMA model at the pre-symptomatic stage, we found that the expression of numerous nuclear encoded mitochondrial genes and vacuolar H+-ATPase genes was significantly down-regulated, while that of histone genes was significantly up-regulated. We previously showed that the uaf-1 gene, encoding key splicing factor U2AF large subunit, could affect the behavior and lifespan of smn-1 mutants. Here, we found that smn-1 and uaf-1 interact to affect the recognition of 3′ and 5′ splice sites in a gene-specific manner. Altogether, our results suggest a functional interaction between smn-1 and uaf-1 in affecting RNA splicing and a potential effect of smn-1 on the expression of mitochondrial and histone genes.
Highlights
Spinal muscular atrophy (SMA) is a severe congenital motor neuron degenerative disease caused by loss-of-function mutations in the survival motor neuron gene 1 (SMN1) (Lefebvre et al, 1995)
Different from mitochondrial and other genes, most histone genes were up-regulated in this model
Our findings suggest that abnormal expression of mitochondrial, V-ATPase and histone genes could be considered in understanding SMA pathogenesis
Summary
Spinal muscular atrophy (SMA) is a severe congenital motor neuron degenerative disease caused by loss-of-function mutations in the survival motor neuron gene 1 (SMN1) (Lefebvre et al, 1995). The broad function of SMN implicates that SMA pathogenesis might involve molecular processes beyond defective RNA splicing and gene expression. Since uaf-1(n4588) can decrease or increase the recognition of 3 splice sites in a gene-specific manner (Ma and Horvitz, 2009; Ma et al, 2011; Zhou et al, 2018), we postulate that this mutation might improve the splicing of a subset of affected genes in smn-1(ok355) mutants, which might compensate the defects in snRNPs and lead to the suppression (Gao et al, 2014). We examined how smn-1 affected C. elegans gene expression and RNA splicing by analyzing the transcriptome of smn-1 mutants at the presymptomatic stage
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