Cell
Volume 148, Issues 1–2, 20 January 2012, Pages 296-308
Journal home page for Cell

Article
Mutation of a U2 snRNA Gene Causes Global Disruption of Alternative Splicing and Neurodegeneration

https://doi.org/10.1016/j.cell.2011.11.057Get rights and content
Under an Elsevier user license
open archive

Summary

Although uridine-rich small nuclear RNAs (U-snRNAs) are essential for pre-mRNA splicing, little is known regarding their function in the regulation of alternative splicing or of the biological consequences of their dysfunction in mammals. Here, we demonstrate that mutation of Rnu2-8, one of the mouse multicopy U2 snRNA genes, causes ataxia and neurodegeneration. Coincident with the observed pathology, the level of mutant U2 RNAs was highest in the cerebellum and increased after granule neuron maturation. Furthermore, neuron loss was strongly dependent on the dosage of mutant and wild-type snRNA genes. Comprehensive transcriptome analysis identified a group of alternative splicing events, including the splicing of small introns, which were disrupted in the mutant cerebellum. Our results suggest that the expression of mammalian U2 snRNA genes, previously presumed to be ubiquitous, is spatially and temporally regulated, and dysfunction of a single U2 snRNA causes neuron degeneration through distortion of pre-mRNA splicing.

Highlights

► Mutation of one of the mouse multicopy U2 snRNA genes causes neurodegeneration ► Expression of this U2 snRNA is spatially and temporally regulated ► Mutant U2 disrupts alternative splicing, including small intron splicing ► Splicing abnormalities and cell death depend on mutant gene dosage

Cited by (0)