Vlgr1 is required for proper stereocilia maturation of cochlear hair cells

Abstract

Very large G-protein coupled receptor (Vlgr1b) is the largest known G-protein coupled receptor.Its function is unknown, although mice with deletion of Vlgr1 (Vlgr1b together with other splicing variants, Vlgr1c, Vlgr1d and Vlgr1e) are known to exhibit audiogenic seizure susceptibility and VLGR1 is reported to be the gene responsible for Usher type 2C syndrome. We demonstrated here that Vlgr1 -mutated mice suffered from a hearing defect because of inner ear dysfunction, as indicated by auditory brainstem response (ABR) and distortion product oto-acoustic emissions (DPOAE). The expression of Vlgr1 was identified in the developing hair cells perinatally, and the translated products were seen to be localized in the base of stereocilia on hair cells using confocal microscopy. This Vlgr1 localization was limited to the base of stereocilia within approximately 200 -400 nm from the apical surface of hair cells, as shown by immunoelectron microscopy. The Vlgr1 -mutated mice exhibited malformation of the stereocilia; the cochlear hair bundles were apparently normal at birth but then became disarranged at postnatal day 8. Furthermore, the stereocilia in the mutant mice became slanted and disarranged thereafter. These results indicate that loss of Vlgr1 resulted in abnormal development of stereocilia formation.

Whirlin and PDZ Domain-containing 7 (PDZD7) Proteins Are Both Required to Form the Quaternary Protein Complex Associated with Usher Syndrome Type 2

“…14), WHRN may prefer to bind to USH2A in photoreceptors. Interestingly, weak and late onset retinal degeneration has been found in Ush2a Ϫ/Ϫ and Whrn neo/neo mice (21,22), whereas no retinal degeneration has been reported in various Gpr98 mutant mice (10,11,16,(41)(42)(43)(44)(45). Therefore, USH2A and WHRN might have more dominant roles than GPR98 and PDZD7 in photoreceptors.…”

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…In the mouse inner ear, ADGRV1 (VLGR1) is essential for the correct organization of signal-uptaking hair bundles during the differentiation of the mechanosensitive hair cells. There, ADGRV1 (VLGR1) was identified as a component of the transient ankle-links, spanning neighboring stereocilia (McGee et al, 2006;Michalski et al, 2007;Yagi et al, 2007). These links stabilize the growing stereocilia during the differentiation of the hair bundle.…”

Development of the hair bundle and mechanotransduction

“…The very large Gprotein coupled receptor 1 (Vlgr1) and usherin are associated with ankle links (McGee et al, 2006, Adato et al, 2005a. In mice, Cdh23, Pcdh15, Ptprq and Vlgr1 are all known to be required for the development and maintenance of hair-bundle structure (DiPalma et al, 2001a;Wilson et al, 2001;Alagramam et al, 2001;McGee et al, 2006;Yagi et al, 2007).…”