The Very Large G-Protein-Coupled Receptor VLGR1: A Component of the Ankle Link Complex Required for the Normal Development of Auditory Hair Bundles

McGee, JoAnn; Goodyear, Richard J.; McMillan, D. Randy; Stauffer, Eric A.; Holt, Jeffrey R.; Locke, Kirsten G.; Birch, David G.; Legan, P. Kevin; White, Perrin C.; Walsh, Edward J.; Richardson, Guy P.

doi:10.1523/jneurosci.0693-06.2006

Cited by 187 publications

(251 citation statements)

References 32 publications

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“…The role of usherin at least is partially redundant, because the hearing loss is moderate and confined to the higher frequency range and hair-cell degeneration is apparent only in the basal turn of the cochlea. In this regard, it is similar to VLGR1, another component of the ankle links (41). The loss of VLGR1 also leads to a hearing loss more pronounced in the higherfrequency range and disruption of cochlear hair cells confined to the basal half (41).…”

Section: Discussionmentioning

confidence: 72%

“…In this regard, it is similar to VLGR1, another component of the ankle links (41). The loss of VLGR1 also leads to a hearing loss more pronounced in the higherfrequency range and disruption of cochlear hair cells confined to the basal half (41).…”

Section: Discussionmentioning

confidence: 72%

“…At least six mouse models with mutations in Usher syndrome genes, both engineered and naturally arisen, have been described. These include models for USH1B (myosin VIIA) (35)(36)(37), USH1C (harmonin) (38), USH1D (cadherin 23) (21, 39), and USH1F (protocadherin 15) (26), USH1G (sans) (40), and USH2C (very large G protein-coupled receptor 1) (41). Hearing defects in these models resembled those of the respective human conditions.…”

Section: Discussionmentioning

confidence: 99%

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Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells

Liu

Bulgakov

Darrow

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

235

261

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Usher syndrome type IIA (USH2A), characterized by progressive photoreceptor degeneration and congenital moderate hearing loss, is the most common subtype of Usher syndrome. In this article, we show that the USH2A protein, also known as usherin, is an exceptionally large (Ϸ600-kDa) matrix protein expressed specifically in retinal photoreceptors and developing cochlear hair cells. In mammalian photoreceptors, usherin is localized to a spatially restricted membrane microdomain at the apical inner segment recess that wraps around the connecting cilia, corresponding to the periciliary ridge complex described for amphibian photoreceptors. In sensory hair cells of the cochlea, it is associated transiently with the hair bundles during postnatal development. Targeted disruption of the Ush2a gene in mice leads to progressive photoreceptor degeneration and a moderate but nonprogressive hearing impairment, mimicking the visual and hearing deficits in USH2A patients. These data suggest that usherin is required for the long-term maintenance of retinal photoreceptors and for the development of cochlear hair cells. We propose a model in which usherin in photoreceptors is tethered via its C terminus to the plasma membrane and its large extracellular domain projecting into the periciliary matrix, where they may interact with the connecting cilium to fulfill important structural or signaling roles.photoreceptor degeneration ͉ retina ͉ retinitis pigmentosa

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells

Liu

Bulgakov

Darrow

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

235

261

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“…7) could provide an environment that favors the formation of flattened blebs. The narrow connecting cilium is linked extracellularly to the IS periciliary ridge (32,33) by fibers containing components of the Usher Syndrome (Ush) protein network, also found in the ankle links of inner ear hair cell cilia (33)(34)(35). The cytoplasmic face of the connecting cilium plasma membrane is linked to microtubules via intraflagellar transport particles.…”

Section: Discussionmentioning

confidence: 99%

Rod disc renewal occurs by evagination of the ciliary plasma membrane that makes cadherin-based contacts with the inner segment

Burgoyne

Meschede

Burden

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

105

110

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The outer segments of vertebrate rod photoreceptors are renewed every 10 d. Outer segment components are transported from the site of synthesis in the inner segment through the connecting cilium, followed by assembly of the highly ordered discs. Two models of assembly of discrete discs involving either successive fusion events between intracellular rhodopsin-bearing vesicles or the evagination of the plasma membrane followed by fusion of adjacent evaginations have been proposed. Here we use immuno-electron microscopy and electron tomography to show that rhodopsin is transported from the inner to the outer segment via the ciliary plasma membrane, subsequently forming successive evaginations that "zipper" up proximally, but at their leading edges are free to make junctions containing the protocadherin, PCDH21, with the inner segment plasma membrane. Given the physical dimensions of the evaginations, coupled with likely instability of the membrane cortex at the distal end of the connecting cilium, we propose that the evagination occurs via a process akin to blebbing and is not driven by actin polymerization. Disassembly of these junctions is accompanied by fusion of the leading edges of successive evaginations to form discrete discs. This fusion is topologically different to that mediated by the membrane fusion proteins, SNAREs, as initial fusion is between exoplasmic leaflets, and is accompanied by gain of the tetraspanin rim protein, peripherin.rod photoreceptors | disc renewal | rhodopsin | protocadherin R od photoreceptors are specialized neurons of the vertebrate retina responsible for vision in dim light. The cylindrical outer segment (OS) contains ∼1,000 stacked discontinuous membranous discs packed with the light-sensitive pigment rhodopsin. This contrasts with the cone OS, which consists of a series of evaginations of the plasma membrane that remain exposed to the extracellular space (1). OS constituents are synthesized in the inner segment (IS) and then transported to the OS via a nonmotile cilium (connecting cilium) that resembles the transition zone of the primary cilium. Because of the high metabolic demand of phototransduction, OS discs undergo daily renewal, whereby the tip (distal end) is shed and phagocytosed by the retinal pigment epithelium while new discs are formed at the base (proximal end) of the OS (2, 3). How these discs are generated and rhodopsin incorporated remains controversial. The evagination model proposes that the ciliary plasma membrane evaginates to form discs that are initially exposed to the extracellular space and then pinch off to form fully closed discs (4). In contrast, the fusion model proposes that discs originate from rhodopsincontaining vesicles, which undergo homotypic fusion to form new discs (5, 6). Conventional electron microscopic (EM) analyses of chemically fixed specimens have clearly shown discs open to the extracellular space at the base of the OS, supporting the evagination model (4,7,8). Furthermore, studies in amphibians have demonstrated that membrane imper...

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“…Whrn, or Pdzd7 gene causes disorganization and gradual degeneration of hair bundles in mice (10,11,16,21,22), which leads to reduction of mechanotransduction responses and hearing loss (10,11,16). Disruption of Whrn or Ush2a expression in the retina results in slow degeneration (21,22); vesicles and vacuoles were found to accumulate around the periciliary membrane complex in Whrn mutant photoreceptors (22).…”

mentioning

confidence: 99%

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

Chen

Zou

Shen

et al. 2014

Journal of Biological Chemistry

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Background: Assembly of the protein complex associated with Usher syndrome type 2 (USH2) is unclear. Results: WHRN and PDZD7 heterodimerization and their interactions with USH2A and GPR98 are required for USH2 complex formation. Conclusion: An USH2 quaternary protein complex may exist in vivo. Significance: This study provides clues to USH2 pathogenesis and may permit the complex reconstitution for therapeutic intervention.

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The Very Large G-Protein-Coupled Receptor VLGR1: A Component of the Ankle Link Complex Required for the Normal Development of Auditory Hair Bundles

Cited by 187 publications

References 32 publications

Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells

Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells

Rod disc renewal occurs by evagination of the ciliary plasma membrane that makes cadherin-based contacts with the inner segment

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

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