Myosin VIIa Participates in Opsin Transport through The Photoreceptor Cilium

Liu, Xinran; Udovichenko, Igor P.; Brown, S. D. M.; Steel, Karen P.; Williams, David S.

doi:10.1523/jneurosci.19-15-06267.1999

Cited by 264 publications

(239 citation statements)

References 46 publications

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“…23 To test if this mutant phenotype had been corrected, we immunogoldlabeled EM sections with opsin antibodies and counted the gold particles in the connecting cilia of photoreceptors underlying corrected RPE cells (i.e. cells containing apical melanosomes).…”

Section: Correction Of Melanosome Mislocalization In Myo7a-null Mice mentioning

confidence: 99%

“…Shaker1 mice carrying the 4626SB allele, an effective null mutation, 15,23 were used on either the C57BL6 or BS (albino) genetic backgrounds, and maintained and genotyped as described. 18,23 They were maintained on a 12-h light/12-h dark cycle, with exposure to 10-50 lux of fluorescent lighting during the light phase, and were treated according to NIH, UCLA and UCSD animal care guidelines.…”

Section: Animalsmentioning

confidence: 99%

“…18,23 They were maintained on a 12-h light/12-h dark cycle, with exposure to 10-50 lux of fluorescent lighting during the light phase, and were treated according to NIH, UCLA and UCSD animal care guidelines. Homozygous mutants were distinguished from the heterozygous controls by their hyperactivity, head-tossing and circling behavior, 13 and/or by a PCR/ restriction digest assay.…”

Section: Animalsmentioning

confidence: 99%

“…Their photoreceptor connecting cilia contain an excess of opsin, indicating an additional role for MYO7A in the renewal of the photoreceptor disk membranes. 23 As Usher 1B appears to result from loss of MYO7A function, 6 the addition of a functional gene (gene replacement therapy) should provide a therapeutic approach. In recent years, significant progress has been made in gene therapy studies, using animal models of inherited retinal degeneration, especially in viral vectormediated replacement of genes normally expressed in the RPE.…”

Section: Introductionmentioning

confidence: 99%

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Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B

Hashimoto¹,

et al. 2007

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One of the most disabling forms of retinal degeneration occurs in Usher syndrome, since it affects patients who already suffer from deafness. Mutations in the myosin VIIa gene (MYO7A) cause a major subtype of Usher syndrome, type 1B. Owing to the loss of function nature of Usher 1B and the relatively large size of MYO7A, we investigated a lentiviral-based gene replacement therapy in the retinas of MYO7A-null mice. Among the different promoters tested, a CMV-MYO7A chimeric promoter produced wild-type levels of MYO7A in cultured RPE cells and retinas in vivo. Efficacy of the lentiviral therapy was tested by using cell-based assays to analyze the correction of previously defined, MYO7A-null phenotypes in the mouse retina. In vitro, defects in phagosome digestion and melanosome motility were rescued in primary cultures of RPE cells. In vivo, the normal apical location of melanosomes in RPE cells was restored, and the abnormal accumulation of opsin in the photoreceptor connecting cilium was corrected. These results demonstrate that a lentiviral vector can accommodate a large cDNA, such as MYO7A, and mediate correction of important cellular functions in the retina, a major site affected in the Usher syndrome. Therefore, a lentiviral-mediated gene replacement strategy for Usher 1B therapy in the retina appears feasible.

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Section: Correction Of Melanosome Mislocalization In Myo7a-null Mice mentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B

Hashimoto¹,

et al. 2007

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“…Although shaker-1 mice exhibit the inner ear defects seen in Usher patients, no retinal degeneration is evident (Hasson et al 1997;Liu et al 1999). A slight slowing of opsin transport along the length of the photoreceptor outer segment was noted, suggesting a potential role for myosin-VIIa in the transport of opsin through the connecting cilium of photoreceptor cells (Liu et al 1999). However, given the tight coupling between opsin delivery to the outer segment and the process of outer segment renewal and RPE phagocytosis, this slowing could also reflect an alteration in the kinetics of RPE phagocytosis of the spent ROS.…”

Section: Introductionmentioning

confidence: 99%

The unconventional myosin-VIIa associates with lysosomes

Soni

Warren

Bucci

et al. 2005

Cell Motil. Cytoskeleton

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Mutations in the myosin-VIIa (MYO7a) gene cause human Usher disease, characterized by hearing impairment and progressive retinal degeneration. In the retina, myosin-VIIa is highly expressed in the retinal pigment epithelium, where it plays a role in the positioning of melanosomes and other digestion organelles. Using a human cultured retinal pigmented epithelia cell line, ARPE-19, as a model system, we have found that a population of myosin-VIIa is associated with cathepsin D-and Rab7-positive lysosomes. Association of myosin-VIIa with lysosomes was Rab7 independent, as dominant negative and dominant active versions of Rab7 did not disrupt myosin-VIIa recruitment to lysosomes. Association of myosin-VIIa with lysosomes was also independent of the actin and microtubule cytoskeleton. Myosin-VIIa copurified with lysosomes on density gradients, and fractionation and extraction experiments suggested that it was tightly associated with the lysosome surface. These studies suggest that myosin-VIIa is a lysosome motor.

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The Usher syndromes

Keats

Corey²

1999

Am. J. Med. Genet.

138

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Mutations in the gene (MYO7A) encoding myosin-VIIa, a member of the large superfamily of myosin motor proteins that move on cytoplasmic actin filaments, and in the USH2A gene, which encodes a novel protein resembling an extracellular matrix protein or a cell adhesion molecule, both cause Usher syndrome (USH), a clinically heterogeneous autosomal recessive disorder comprising hearing and visual impairment. Patients with USH1 have severe to profound congenital hearing impairment, vestibular dysfunction, and retinal degeneration beginning in childhood, while those with USH2 have moderate to severe hearing impairment, normal vestibular function, and later onset of retinal degeneration. USH3 is characterized by progressive hearing loss and variable age of onset of retinal degeneration. The phenotype resulting from MYO7A and USH2A mutations is variable. While most MYO7A mutations cause USH1, some cause nonsyndromic hearing impairment, and one USH3 phenotype has been described. USH2A mutations cause atypical USH as well as USH2. MYO7A is on chromosome region 11q13 and USH2A is on 1q41. Seven other USH genes have been mapped but have not yet been identified. USH1A, USH1C, USH1D, USH1E, and USH1F have been assigned to chromosome bands 14q32, 11p15.1, 10q, 21q21, and 10, respectively, while USH2B is on 5q, and USH3 is at 3q21-q25. Myosin VIIa mutations also result in the shaker-1 (sh1) mouse, providing a model for functional studies. One possibility is that myosin-VIIa is required for linking stereocilia in the sensory hair bundle; another is that it may be needed for membrane trafficking. The ongoing studies of myosin-VIIa, the USH2A protein, and the yet to be identified proteins encoded by the other USH genes will advance understanding of the Usher syndromes and contribute to the development of effective therapies. Am. J. Med. Genet. (Semin. Med. Genet.) 89:158-166, 1999.

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Myosin VIIa Participates in Opsin Transport through The Photoreceptor Cilium

Cited by 264 publications

References 46 publications

Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B

Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B

The unconventional myosin-VIIa associates with lysosomes

The Usher syndromes

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