A mutation in the Srrm4 gene causes alternative splicing defects and deafness in Bronx waltzer mice.
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA154337PRJNA148555PRJNA154335
ORGANISM(S): Mus musculus
PROVIDER: GSE33591 | GEO | 2012/10/21
SECONDARY ACCESSION(S): PRJNA148555
REPOSITORIES: GEO
Similar Datasets
Project description:Sensory hair cells are essential for hearing and balance. Their development from epithelial precursors has been extensively characterized with respect to transcriptional regulation, but not in terms of posttranscriptional influences. Here we report on the identification and functional characterization of an alternative-splicing regulator whose inactivation is responsible for defective hair-cell development, deafness, and impaired balance in the spontaneous mutant Bronx waltzer (bv) mouse. We used positional cloning and transgenic rescue to locate the bv mutation to the splicing factor-encoding gene Ser/Arg repetitive matrix 4 (Srrm4). Transcriptome-wide analysis of pre-mRNA splicing in the sensory patches of embryonic inner ears revealed that specific alternative exons were skipped at abnormally high rates in the bv mice. Minigene experiments in a heterologous expression system confirmed that these skipped exons require Srrm4 for inclusion into the mature mRNA. Sequence analysis and mutagenesis experiments showed that the affected transcripts share a novel motif that is necessary for the Srrm4-dependent alternative splicing. Functional annotations and protein-protein interaction data indicated that the encoded proteins cluster in the secretion and neurotransmission pathways. In addition, the splicing of a few transcriptional regulators was found to be Srrm4 dependent, and several of the genes known to be targeted by these regulators were expressed at reduced levels in the bv mice. Although Srrm4 expression was detected in neural tissues as well as hair cells, analyses of the bv mouse cerebellum and neocortex failed to detect splicing defects. Our data suggest that Srrm4 function is critical in the hearing and balance organs, but not in all neural tissues. Srrm4 is the first alternative-splicing regulator to be associated with hearing, and the analysis of bv mice provides exon-level insights into hair-cell development.
| S-EPMC3464207 | biostudies-literature
Project description:The spontaneous mutant Bronx waltzer (bv) mouse line is characterized by deafness and balance defect. We located the bv mutation to the Srrm4 gene which encodes a regulator of alternative pre-mRNA splicing. We found that Srrm4 is expressed in balance and hearing organs (i.e. in the vestibular maculas and the cochlea). Srrm4 is also expressed in the central nervous system including the cerebellum. To identify potential splicing defects in bv/bv mice, we analyzed RNA samples from the vestibular maculas and cerebellums of bv/bv mice and control (bv/+) littermates, using mouse exon junction microarrays (MJAY). In this dataset, we include probe-set level data obtained from cerebellar samples. The processed data represent probe-set intensities that have been normalized to gene expression levels. 8 total samples were analyzed in this series: cerebellums from 4 heterozygous (bv/+) and 4 homozygous (bv/bv) mice at P15.
2012-10-21 | E-GEOD-33589 | biostudies-arrayexpress
Project description:The spontaneous mutant Bronx waltzer (bv) mouse line is characterized by deafness and balance defect. We located the bv mutation to the Srrm4 gene which encodes a regulator of alternative pre-mRNA splicing. We found that Srrm4 is expressed in balance and hearing organs (i.e. in the vestibular maculas and the cochlea). Srrm4 is also expressed in the central nervous system including the cerebellum. To identify potential splicing defects in bv/bv mice, we analyzed RNA samples from the vestibular maculas and cerebellums of bv/bv mice and control (bv/+) littermates, using mouse exon junction microarrays (MJAY). In this dataset, we include probe-set level data obtained from cerebellar samples. The processed data represent probe-set intensities that have been normalized to gene expression levels.
2012-10-21 | GSE33589 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-06-28 | GSE111606 | GEO
Project description:A mutation in the Srrm4 gene causes alternative splicing defects and deafness in Bronx waltzer mice.
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