title: Genome-Wide Association Analysis Identifies Dcc as an Essential Factor in the Innervation of the Peripheral Vestibular System in Inbred Mice.
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.
authors.affiliation: USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Zilkha Neurogenetic Institute, Keck Medicine of USC, University of Southern California, Los Angeles, CA, USA.
authors.forename: Pezhman
authors.initials: P
authors.lastname: Salehi
authors.affiliation: USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Zilkha Neurogenetic Institute, Keck Medicine of USC, University of Southern California, Los Angeles, CA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Myint
authors.affiliation: Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Young J
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Zilkha Neurogenetic Institute, Keck Medicine of USC, University of Southern California, Los Angeles, CA, USA.
authors.forename: Marshall X
authors.initials: MX
authors.lastname: Ge
authors.affiliation: USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Zilkha Neurogenetic Institute, Keck Medicine of USC, University of Southern California, Los Angeles, CA, USA.|Graduate Program in Surgical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Joel
authors.initials: J
authors.lastname: Lavinsky
authors.affiliation: USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Zilkha Neurogenetic Institute, Keck Medicine of USC, University of Southern California, Los Angeles, CA, USA.|Department of Internal Medicine, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Ho
authors.affiliation: Department of Preventive Medicine and Institute for Genetic Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Crow
authors.affiliation: USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Zilkha Neurogenetic Institute, Keck Medicine of USC, University of Southern California, Los Angeles, CA, USA.
authors.forename: Charlene
authors.initials: C
authors.lastname: Cruz
authors.affiliation: USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Zilkha Neurogenetic Institute, Keck Medicine of USC, University of Southern California, Los Angeles, CA, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Monges-Hernadez
authors.affiliation: USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Zilkha Neurogenetic Institute, Keck Medicine of USC, University of Southern California, Los Angeles, CA, USA.
authors.forename: Juemei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Preventive Medicine and Institute for Genetic Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Jaana
authors.initials: J
authors.lastname: Hartiala
authors.affiliation: Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Li I
authors.initials: LI
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine and Institute for Genetic Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
authors.affiliation: Department of Preventive Medicine and Institute for Genetic Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.|Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Zilkha Neurogenetic Institute, Keck Medicine of USC, University of Southern California, Los Angeles, CA, USA. takahiro.ohyama@med.usc.edu.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ohyama
authors.affiliation: USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Zilkha Neurogenetic Institute, Keck Medicine of USC, University of Southern California, Los Angeles, CA, USA. rick.friedman@med.usc.edu.|Department of Otolaryngology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. rick.friedman@med.usc.edu.
authors.forename: Rick A
authors.initials: RA
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000075389:DCC Receptor / Q000502:physiology*; D005071:Evoked Potentials; D005260:Female; D055106:Genome-Wide Association Study; D008297:Male; D051379:Mice; D014722:Vestibule, Labyrinth / Q000294:innervation* / Q000378:metabolism
chemical_list: D000075389:DCC Receptor; C501910:Dcc protein, mouse
keywords: Hybrid Mouse Diversity Panel; axonal migration; crista; deleted in colorectal carcinoma (Dcc); genome-wide association study; utricle; vestibular ganglia; vestibular sensory evoked potential; vestibular system