Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation

Satō, Shigeru; Omori, Yoshihiro; Katoh, Kimiko; Kondo, Mineo; Kanagawa, Motoi; Miyata, Kanji; Funabiki, Kazuo; Koyasu, Toshiyuki; Kajimura, Naoko; Miyoshi, Tomomitsu; Sawai, Hirozumi; Kobayashi, Kenzo; Tani, Akiko; Toda, Tatsushi; Usukura, Jiro; Tano, Yasuo; Fujikado, Takashi; Furukawa, Takahisa

doi:10.1038/nn.2160

Cited by 252 publications

(299 citation statements)

References 41 publications

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“…In the course of a microarray screening for genes specifically expressed in photoreceptors (20), we found that the Mak transcript is markedly reduced in the orthodenticle homeobox 2 (Otx2) conditional knockout (CKO) retina in which most of the photoreceptors are converted to amacrine-like cells (21). We confirmed by quantitative PCR analysis that Mak expression is markedly decreased in the Otx2 CKO retina at postnatal day 12 (P12) (Fig.…”

Section: Resultsmentioning

confidence: 77%

Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival

Omori

Chaya

Katoh³

et al. 2010

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

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126

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Cilia function as cell sensors in many organs, and their disorders are referred to as "ciliopathies." Although ciliary components and transport machinery have been well studied, regulatory mechanisms of ciliary formation and maintenance are poorly understood. Here we show that male germ cell-associated kinase (Mak) regulates retinal photoreceptor ciliary length and subcompartmentalization. Mak was localized both in the connecting cilia and outer-segment axonemes of photoreceptor cells. In the Mak-null retina, photoreceptors exhibit elongated cilia and progressive degeneration. We observed accumulation of intraflagellar transport 88 (IFT88) and IFT57, expansion of kinesin family member 3A (Kif3a), and acetylated α-tubulin signals in the Mak-null photoreceptor cilia. We found abnormal rhodopsin accumulation in the Mak-null photoreceptor cell bodies at postnatal day 14. In addition, overexpression of retinitis pigmentosa 1 (RP1), a microtubule-associated protein localized in outer-segment axonemes, induced ciliary elongation, and Mak coexpression rescued excessive ciliary elongation by RP1. The RP1 N-terminal portion induces ciliary elongation and increased intensity of acetylated α-tubulin labeling in the cells and is phosphorylated by Mak. These results suggest that Mak is essential for the regulation of ciliary length and is required for the long-term survival of photoreceptors.

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Section: Resultsmentioning

confidence: 77%

Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival

Omori

Chaya

Katoh³

et al. 2010

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

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126

180

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“…Photoreceptor axonal terminals form ribbon synapses in the OPL, which connect photoreceptor presynapses with the dendritic terminal of both bipolar cells and horizontal cells (tom Dieck and Brandstätter, 2006). We previously reported that an extracellular matrix protein, Pikachurin, is essential for the proper formation of ribbon synaptic structures (Sato et al, 2008). Pikachurin Ϫ/ Ϫ mice showed a reduced amplitude and prolonged implicit time of the b-wave similar to other mutant mice with perturbed DGC formation.…”

Section: Introductionmentioning

confidence: 89%

“…Dystroglycan (DG), a key component of the DGC, consists of an extracellular ␣-DG subunit and a transmembrane ␤-DG subunit. Several extracellular ligands for ␣-DG, including laminin, agrin, perlecan, and Pikachurin, have been reported (Ibraghimov-Beskrovnaya et al, 1992;Ervasti and Campbell, 1993;Gee et al, 1994;Peng et al, 1998;Sugita et al, 2001;Sato et al, 2008). These DG ligands commonly contain Laminin G repeats, and these domains physically interact with DG.…”

Section: Introductionmentioning

confidence: 99%

“…Pikachurin Ϫ/ Ϫ mice showed a reduced amplitude and prolonged implicit time of the b-wave similar to other mutant mice with perturbed DGC formation. Pikachurin physically interacts with DG, and proper glycosylation of DG is required for its interaction with Pikachurin (Sato et al, 2008;Kanagawa et al, 2010). It was reported that the loss of DG in Müller glial cells causes ERG abnormality (Satz et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Presynaptic Dystroglycan–Pikachurin Complex Regulates the Proper Synaptic Connection between Retinal Photoreceptor and Bipolar Cells

Omori¹,

Araki²,

Chaya³

et al. 2012

J. Neurosci.

104

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Dystroglycan (DG) is a key component of the dystrophin-glycoprotein complex (DGC)at the neuromuscular junction postsynapse. In the mouse retina, the DGC is localized at the presynapse of photoreceptor cells, however, the function of presynaptic DGC is poorly understood. Here, we developed and analyzed retinal photoreceptor-specific DG conditional knock-out (DG CKO) mice. We found that the DG CKO retina showed a reduced amplitude and a prolonged implicit time of the ERG b-wave. Electron microscopic analysis revealed that bipolar dendrite invagination into the photoreceptor terminus is perturbed in the DG CKO retina. In the DG CKO retina, pikachurin, a DG ligand in the retina, is markedly decreased at photoreceptor synapses. Interestingly, in the Pikachurin Ϫ/Ϫ retina, the DG signal at the ribbon synaptic terminus was severely reduced, suggesting that pikachurin is required for the presynaptic accumulation of DG at the photoreceptor synaptic terminus, and conversely DG is required for pikachurin accumulation. Furthermore, we found that overexpression of pikachurin induces formation and clustering of a DG-pikachurin complex on the cell surface. The Laminin G repeats of pikachurin, which are critical for its oligomerization and interaction with DG, were essential for the clustering of the DG-pikachurin complex as well. These results suggest that oligomerization of pikachurin and its interaction with DG causes DG assembly on the synapse surface of the photoreceptor synaptic terminals. Our results reveal that the presynaptic interaction of pikachurin with DG at photoreceptor terminals is essential for both the formation of proper photoreceptor ribbon synaptic structures and normal retinal electrophysiology.

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“…The glycan chains of the central mucin domain of ␣-dystroglycan are known to mediate binding to components such as laminin (Ervasti and Campbell, 1993), perlecan (Peng et al, 1998) agrin (Bowe et al, 1994;Campanelli et al, 1994;Gee et al, 1994), neurexin in the brain (Sugita et al, 2001) and pikachurin in the eye (Sato et al, 2008). Aberrant glycosylation of ␣-dystroglycan is thought to be central to the pathogenesis of the muscular dystrophy and the brain abnormalities manifested by patients (cobblestone lissencephaly) and animal models with severe forms of dystroglycanopathy (Michele et al, 2002;Michele and Campbell, 2003;Hewitt, 2009;Yoshida-Moriguchi et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Fukutin-Related Protein Alters the Deposition of Laminin in the Eye and Brain

Ackroyd¹,

Whitmore²,

Prior³

et al. 2011

J. Neurosci.

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Mutations in fukutin-related protein (FKRP) are responsible for a common group of muscular dystrophies ranging from adult onset limb girdle muscular dystrophies to severe congenital forms with associated structural brain involvement. The defining feature of this group of disorders is the hypoglycosylation of ␣-dystroglycan and its inability to effectively bind extracellular matrix ligands such as laminin ␣2. However, ␣-dystroglycan has the potential to interact with a number of laminin isoforms many of which are basement membrane/ tissue specific and developmentally regulated. To further investigate this we evaluated laminin ␣-chain expression in the cerebral cortex and eye of our FKRP knock-down mouse (FKRP KD ). These mice showed a marked disturbance in the deposition of laminin ␣-chains including ␣1, ␣2, ␣4, and ␣5, although only laminin ␣1-and ␥1-chain mRNA expression was significantly upregulated relative to controls. Moreover, there was a diffuse pattern of laminin deposition below the pial surface which correlated with an abrupt termination of many of the radial glial cells. This along with the pial basement membrane defects, contributed to the abnormal positioning of both early-and late-born neurons. Defects in the inner limiting membrane of the eye were associated with a reduction of laminin ␣1 demonstrating the involvement of the ␣-dystroglycan:laminin ␣1 axis in the disease process. These observations demonstrate for the first time that a reduction in Fkrp influences the ability of tissue-specific forms of ␣-dystroglycan to direct the deposition of several laminin isoforms in the formation of different basement membranes.

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Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation

Cited by 252 publications

References 41 publications

Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival

Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival

Presynaptic Dystroglycan–Pikachurin Complex Regulates the Proper Synaptic Connection between Retinal Photoreceptor and Bipolar Cells

Fukutin-Related Protein Alters the Deposition of Laminin in the Eye and Brain

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