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Genome-Wide Association Analysis Identifies Dcc as an Essential Factor in the Innervation of the Peripheral Vestibular System in Inbred Mice
- Source :
- Journal of the Association for Research in Otolaryngology : JARO. 17(5)
- Publication Year :
- 2016
-
Abstract
- This study aimed to investigate the genetic causes of vestibular dysfunction. We used vestibular sensory-evoked potentials (VsEPs) to characterize the vestibular function of 35 inbred mouse strains selected from the Hybrid Mouse Diversity Panel and demonstrated strain-dependent phenotypic variation in vestibular function. Using these phenotypic data, we performed the first genome-wide association study controlling for population structure that has revealed two highly suggestive loci, one of which lies within a haplotype block containing five genes (Stard6, 4930503L19Rik, Poli, Mbd2, Dcc) on Chr. 18 (peak SNP rs29632020), one gene, deleted in colorectal carcinoma (Dcc) has a well-established role in nervous system development. An in-depth analysis of Dcc-deficient mice demonstrated elevation in mean VsEP threshold for Dcc +/− mice (−11.86 dB) compared to wild-type (−9.68 dB) littermates. Synaptic ribbon studies revealed Dcc −/− (P0) and Dcc +/− (6-week-old) mice showed lower density of the presynaptic marker (CtBP2) as compared to wild-type controls. Vestibular ganglion cell counts of Dcc −/− (P0) was lower than controls. Whole-mount preparations showed abnormal innervation of the utricle, saccule, and crista ampullaris at E14.5, E16.5, and E18.5. Postnatal studies were limited by the perinatal lethality in Dcc −/− mice. Expression analyses using in situ hybridization and immunohistochemistry showed Dcc expression in the mouse vestibular ganglion (E15.5), and utricle and crista ampullaris (6-week-old), respectively. In summary, we report the first GWAS for vestibular functional variation in inbred mice and provide evidence for the role of Dcc in the normal innervation of the peripheral vestibular system.
- Subjects :
- 0301 basic medicine
Male
Deleted in Colorectal Cancer
Scarpa's ganglion
In situ hybridization
Biology
03 medical and health sciences
Mice
Utricle
medicine
Animals
Evoked Potentials
Synaptic ribbon
Vestibular system
Crista ampullaris
fungi
Anatomy
DCC Receptor
Molecular biology
Sensory Systems
030104 developmental biology
medicine.anatomical_structure
Otorhinolaryngology
Female
Saccule
sense organs
Vestibule, Labyrinth
Genome-Wide Association Study
Research Article
Subjects
Details
- ISSN :
- 14387573
- Volume :
- 17
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Journal of the Association for Research in Otolaryngology : JARO
- Accession number :
- edsair.doi.dedup.....9cca7c7ec1fa8082826a68d6d14b7ebf