19 results on '"Hicks, Wanda L."'
Search Results
2. Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration
- Author
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Zhao, Lihong, Spassieva, Stefka, Gable, Kenneth, Gupta, Sita D., Shi, Lan-Ying, Wang, Jieping, Bielawski, Jacek, Hicks, Wanda L., Krebs, Mark P., Naggert, Juergen, Hannun, Yusuf A., Dunn, Teresa M., and Nishina, Patsy M.
- Published
- 2015
3. Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation
- Author
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Collin, Gayle B., Hubmacher, Dirk, Charette, Jeremy R., Hicks, Wanda L., Stone, Lisa, Yu, Minzhong, Naggert, Jürgen K., Krebs, Mark P., Peachey, Neal S., Apte, Suneel S., and Nishina, Patsy M.
- Published
- 2015
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- View/download PDF
4. Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice
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Boldt, Karsten, Mans, Dorus A., Won, Jungyeon, van Reeuwijk, Jeroen, Vogt, Andreas, Kinkl, Norbert, Letteboer, Stef J.F., Hicks, Wanda L., Hurd, Ron E., Naggert, Jurgen K., Texier, Yves, den Hollander, Anneke I., Koenekoop, Robert K., Bennett, Jean, Cremers, Frans P.M., Gloeckner, Christian J., Nishina, Patsy M., Roepman, Ronald, and Ueffing, Marius
- Subjects
Blindness ,Genetic disorders ,Health care industry - Abstract
The mutations that cause Leber congenital amaurosis (LCA) lead to photoreceptor cell death at an early age, causing childhood blindness. To unravel the molecular basis of LCA, we analyzed how [...]
- Published
- 2011
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5. NPHP4 is necessary for normal photoreceptor ribbon synapse maintenance and outer segment formation, and for sperm development
- Author
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Won, Jungyeon, de Evsikova, Caralina Marín, Smith, Richard S., Hicks, Wanda L., Edwards, Malia M., Longo-Guess, Chantal, Li, Tiansen, Naggert, Jürgen K., and Nishina, Patsy M.
- Published
- 2011
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6. RPGRIP1 is essential for normal rod photoreceptor outer segment elaboration and morphogenesis
- Author
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Won, Jungyeon, Gifford, Elaine, Smith, Richard S., Yi, Haiqing, Ferreira, Paulo A., Hicks, Wanda L., Li, Tiansen, Naggert, Jürgen K., and Nishina, Patsy M.
- Published
- 2009
7. Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses
- Author
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Maddox, Dennis M., Vessey, Kirstan A., Yarbrough, Gary L., Invergo, Brandon M., Cantrell, Donald R., Inayat, Samsoon, Balannik, Victoria, Hicks, Wanda L., Hawes, Norman L., Byers, Shannon, Smith, Richard S., Hurd, Ron, Howell, Douglas, Gregg, Ronald G., Chang, Bo, Naggert, Jürgen K., Troy, John B., Pinto, Lawrence H., Nishina, Patsy M., and McCall, Maureen A.
- Published
- 2008
8. An FRMD4B variant suppresses dysplastic photoreceptor lesions in models of enhanced S-cone syndrome and of Nrl deficiency.
- Author
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Kong, Yang, Zhao, Lihong, Charette, Jeremy R, Hicks, Wanda L, Stone, Lisa, Nishina, Patsy M, and Naggert, Jürgen K
- Published
- 2018
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9. Mouse models of human ocular disease for translational research.
- Author
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Krebs, Mark P., Collin, Gayle B., Hicks, Wanda L., Yu, Minzhong, Charette, Jeremy R., Shi, Lan Ying, Wang, Jieping, Naggert, Jürgen K., Peachey, Neal S., and Nishina, Patsy M.
- Subjects
EYE diseases ,DEGENERATION (Pathology) ,ANIMAL models in research ,GENETIC mutation ,LABORATORY mice - Abstract
Mouse models provide a valuable tool for exploring pathogenic mechanisms underlying inherited human disease. Here, we describe seven mouse models identified through the Translational Vision Research Models (TVRM) program, each carrying a new allele of a gene previously linked to retinal developmental and/or degenerative disease. The mutations include four alleles of three genes linked to human nonsyndromic ocular diseases (Aipl1
tvrm119 , Aipl1tvrm127 , Rpgrip1tvrm111 , RhoTvrm334 ) and three alleles of genes associated with human syndromic diseases that exhibit ocular phentoypes (Alms1tvrm102 , Clcn2nmf289 , Fkrptvrm53 ). Phenotypic characterization of each model is provided in the context of existing literature, in some cases refining our current understanding of specific disease attributes. These murine models, on fixed genetic backgrounds, are available for distribution upon request and may be useful for understanding the function of the gene in the retina, the pathological mechanisms induced by its disruption, and for testing experimental approaches to treat the corresponding human ocular diseases. [ABSTRACT FROM AUTHOR]- Published
- 2017
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- View/download PDF
10. Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration.
- Author
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Lihong Zhao, Spassieva, Stefka, Gable, Kenneth, Gupta, Sita D., Lan-Ying Shi, Jieping Wang, Bielawski, Jacek, Hicks, Wanda L., Krebs, Mark P., Naggert, Juergen, Hannun, Yusuf A., Dunn, Teresa M., and Nishina, Patsy M.
- Subjects
SPHINGOLIPIDS ,GENETIC mutation ,HOMEOSTASIS ,PROTEIN research ,NEURODEGENERATION - Abstract
Sphingolipids typically have an 18-carbon (C18) sphingoid long chain base (LCB) backbone. Although sphingolipids with LCBs of other chain lengths have been identified, the functional significance of these low-abundance sphingolipids is unknown. The LCB chain length is determined by serine palmitoyltransferase (SPT) isoenzymes, which are trimeric proteins composed of two large subunits (SPTLC1 and SPTLC2 or SPTLC3) and a small subunit (SPTssa or SPTssb). Here we report the identification of an Sptssb mutation, Stellar (Stl), which increased the SPT affinity toward the C18 fatty acyl-CoA substrate by twofold and significantly elevated 20-carbon (C20) LCB production in the mutant mouse brain and eye, resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration. Our work demonstrates that SPT small subunits play a major role in controlling SPT activity and substrate affinity, and in specifying sphingolipid LCB chain length in vivo. Moreover, our studies also suggest that excessive C20 LCBs or C20 LCB-containing sphingolipids impair protein homeostasis and neural functions. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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11. Gene Profiling of Postnatal Mfrprd6 Mutant Eyes Reveals Differential Accumulation of Prss56, Visual Cycle and Phototransduction mRNAs.
- Author
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Soundararajan, Ramani, Won, Jungyeon, Stearns, Timothy M., Charette, Jeremy R., Hicks, Wanda L., Collin, Gayle B., Naggert, Jürgen K., Krebs, Mark P., and Nishina, Patsy M.
- Subjects
DATA analysis ,PHOTORECEPTORS ,MICROPHTHALMIA ,MESSENGER RNA ,IN situ hybridization ,RETINAL degeneration ,RETINITIS pigmentosa ,PATIENTS - Abstract
Mutations in the membrane frizzled-related protein (MFRP/Mfrp) gene, specifically expressed in the retinal pigment epithelium (RPE) and ciliary body, cause nanophthalmia or posterior microphthalmia with retinitis pigmentosa in humans, and photoreceptor degeneration in mice. To better understand MFRP function, microarray analysis was performed on eyes of homozygous Mfrp
rd6 and C57BL/6J mice at postnatal days (P) 0 and P14, prior to photoreceptor loss. Data analysis revealed no changes at P0 but significant differences in RPE and retina-specific transcripts at P14, suggesting a postnatal influence of the Mfrprd6 allele. A subset of these transcripts was validated by quantitative real-time PCR (qRT-PCR). In Mfrprd6 eyes, a significant 1.5- to 2.0-fold decrease was observed among transcripts of genes linked to retinal degeneration, including those involved in visual cycle (Rpe65, Lrat, Rgr), phototransduction (Pde6a, Guca1b, Rgs9), and photoreceptor disc morphogenesis (Rpgrip1 and Fscn2). Levels of RPE65 were significantly decreased by 2.0-fold. Transcripts of Prss56, a gene associated with angle-closure glaucoma, posterior microphthalmia and myopia, were increased in Mfrprd6 eyes by 17-fold. Validation by qRT-PCR indicated a 3.5-, 14- and 70-fold accumulation of Prss56 transcripts relative to controls at P7, P14 and P21, respectively. This trend was not observed in other RPE or photoreceptor mutant mouse models with similar disease progression, suggesting that Prss56 upregulation is a specific attribute of the disruption of Mfrp. Prss56 and Glul in situ hybridization directly identified Müller glia in the inner nuclear layer as the cell type expressing Prss56. In summary, the Mfrprd6 allele causes significant postnatal changes in transcript and protein levels in the retina and RPE. The link between Mfrp deficiency and Prss56 up-regulation, together with the genetic association of human MFRP or PRSS56 variants and ocular size, raises the possibility that these genes are part of a regulatory network influencing postnatal posterior eye development. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
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12. Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses.
- Author
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Maddox, Dennis M., Vessey, Kirstan A., Yarbrough, Gary L., Invergo, Brandon M., Cantrell, Donald R., Inayat, Samsoon, Balannik, Victoria, Hicks, Wanda L., Hawes, Norman L., Byers, Shannon, Smith, Richard S., Hurd, Ron, Howell, Douglas, Gregg, Ronald G., Chang, Bo, Naggert, Jürgen K., Troy, John B., Pinto, Lawrence H., Nishina, Patsy M., and McCall, Maureen A.
- Abstract
An electroretinogram (ERG) screen identified a mouse with a normal a-wave but lacking a b-wave, and as such it was designated no b-wave3 ( nob3). The nob3 phenotype mapped to chromosome 11 in a region containing the metabotropic glutamate receptor 6 gene ( Grm6). Sequence analyses of cDNA identified a splicing error in Grm6, introducing an insertion and an early stop codon into the mRNA of affected mice (designated Grm6
nob3 ). Immunohistochemistry of the Grm6nob3 retina showed that GRM6 was absent. The ERG and visual behaviour abnormalities of Grm6nob3 mice are similar to Grm6nob4 animals, and similar deficits were seen in compound heterozygotes ( Grm6nob4/nob3 ), indicating that Grm6nob3 is allelic to Grm6nob4 . Visual responses of Grm6nob3 retinal ganglion cells (RGCs) to light onset were abnormal. Grm6nob3 ON RGCs were rarely recorded, but when they were, had ill-defined receptive field (RF) centres and delayed onset latencies. When Grm6nob3 OFF-centre RGC responses were evoked by full-field stimulation, significantly fewer converted that response to OFF/ON compared to Grm6nob4 RGCs. Grm6nob4/nob3 RGC responses verified the conclusion that the two mutants are allelic. We propose that Grm6nob3 is a new model of human autosomal recessive congenital stationary night blindness. However, an allelic difference between Grm6nob3 and Grm6nob4 creates a disparity in inner retinal processing. Because the localization of GRM6 is limited to bipolar cells in the On pathway, the observed difference between RGCs in these mutants is likely to arise from differences in their inputs. [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
13. Mutations of the Opsin Gene (Y102H and I307 N) Lead to Light-induced Degeneration of Photoreceptors and Constitutive Activation of Phototransductjon in Mice.
- Author
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Budzynski, Ewa, Gross, Alecia K., McAIear, Suzanne D., Peachey, Neal S., ShukIa, Meera, Feng He, Edwards, Malia, Jungyeon Won, Hicks, Wanda L., Wensel, Theodore G., Naggert, Jurgen K., and Nishina, Patsy M.
- Subjects
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OPSINS , *GENETIC mutation , *GENES , *RHODOPSIN , *RETINITIS pigmentosa , *TRANSGENIC mice , *LABORATORY mice - Abstract
Mutations in the Rhodopsin (Rho) gene can lead to autosomal dominant retinitis pigmentosa (RP) in humans. Transgenic mouse models with mutations in Rho have been developed to study the disease. However, it is difficult to know the source of the photoreceptor (PR) degeneration in these transgenic models because overexpression of wild type (WT) Rho alone can lead to PR degeneration. Here, we report two chemically mutagenized mouse models carrying point mutations in Rho (Tvrm1 with an Y102H mutation and Tvrm4 with an 1307N mutation). Both mutants express normal levels of rhodopsin that localize to the PR outer segments and do not exhibit PR degeneration when raised in ambient mouse room lighting; however, severe PR degeneration is observed after short exposures to bright light. Both mutations also cause a delay in recovery following bleaching. This defect might be due to a slower rate of chromophore binding by the mutant opsins compared with the WT form, and an increased rate of transducin activation by the unbound mutant opsins, which leads to a constitutive activation of the phototransduction cascade as revealed by in vitro biochemical assays. The mutant-free opsins produced by the respective mutant Rho genes appear to be more toxic to PRs, as Tvrm1 and Tvrm4 mutants lacking the 11-cis chromophore degenerate faster than mice expressing WT opsin that also lack the chromophore. Because of their phenotypic similarity to humans with Bi Rho mutations, these mutants will be important tools in examining mechanisms underlying Rho-induced RP and for testing therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
14. Mutations in Lamal Disrupt Retinal Vascular Development and Inner Limiting Membrane Formation.
- Author
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Edwards, Malia M., Mammadova-Bach, Elmina, Alpy, Fabien, KIein, Annick, Hicks, Wanda L., Roux, Michel, Simon-Assmann, Patricia, Smith, Richard S., Orend, Gertraud, Jiang Wu, Peachey, Neal S., Naggert, Jürgen K., Lefebvre, Olivier, and Nishina, Patsy M.
- Subjects
- *
RETINAL diseases , *GENETIC mutation , *LABORATORY mice , *BIOLOGICAL membranes , *ASTROCYTES , *IMMUNOHISTOCHEMISTRY - Abstract
The Neuromutagenesis Facility at the Jackson Laboratory generated a mouse model of retinal vasculopathy, nmf223, which is characterized clinically by vitreal fibroplasia and vessel tortuosity. nmf223 homozygotes also have reduced electroretinogram responses, which are coupled histologically with a thinning of the inner nuclear layer. The nmf223 locus was mapped to chromosome 17, and a missense mutation was identified in Lama1 that leads to the substitution of cysteine for a tyrosine at amino acid 265 of laminin cd, a basement membrane protein. Despite normal localization of laminin α1 and other components of the inner limiting membrane, a reduced integrity of this structure was suggested by ectopic cells and blood vessels within the vitreous. Immunohistochemical characterization of nmf223 homozygous retinas demonstrated the abnormal migration of retinal astrocytes into the vitreous along with the persistence of hyaloid vasculature. The Y265C mutation significantly reduced laminin N-terminal domain (LN) interactions in a bacterial twohybrid system. Therefore, this mutation could affect interactions between laminin α1 and other laminin chains. To expand upon these findings, a Lama1 null mutant, Lama1tm1.1Olf, was generated that exhibits a similar but more severe retinal phenotype than that seen in nmj223 homozygotes. The increased severity of the Lama1 null mutant phenotype is probably due to the complete loss of the inner limiting membrane in these mice. This first report of viable Lama1 mouse mutants emphasizes the importance of this gene in retinal development. The data presented herein suggest that hypomorphic mutations in human LAMA1 could lead to retinal disease. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
15. Gene profiling of postnatal Mfrprd6 mutant eyes reveals differential accumulation of Prss56, visual cycle and phototransduction mRNAs.
- Author
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Soundararajan R, Won J, Stearns TM, Charette JR, Hicks WL, Collin GB, Naggert JK, Krebs MP, and Nishina PM
- Subjects
- Animals, Gene Expression Profiling, Humans, Mice, Mice, Mutant Strains, Microphthalmos genetics, Microphthalmos metabolism, Microphthalmos pathology, Retina pathology, Retinitis Pigmentosa genetics, Retinitis Pigmentosa metabolism, Retinitis Pigmentosa pathology, Serine Proteases genetics, Eye Proteins genetics, Eye Proteins metabolism, Gene Expression Regulation, Enzymologic, Membrane Proteins genetics, Membrane Proteins metabolism, Retina metabolism, Serine Proteases biosynthesis, Up-Regulation, Vision, Ocular genetics
- Abstract
Mutations in the membrane frizzled-related protein (MFRP/Mfrp) gene, specifically expressed in the retinal pigment epithelium (RPE) and ciliary body, cause nanophthalmia or posterior microphthalmia with retinitis pigmentosa in humans, and photoreceptor degeneration in mice. To better understand MFRP function, microarray analysis was performed on eyes of homozygous Mfrprd6 and C57BL/6J mice at postnatal days (P) 0 and P14, prior to photoreceptor loss. Data analysis revealed no changes at P0 but significant differences in RPE and retina-specific transcripts at P14, suggesting a postnatal influence of the Mfrprd6 allele. A subset of these transcripts was validated by quantitative real-time PCR (qRT-PCR). In Mfrprd6 eyes, a significant 1.5- to 2.0-fold decrease was observed among transcripts of genes linked to retinal degeneration, including those involved in visual cycle (Rpe65, Lrat, Rgr), phototransduction (Pde6a, Guca1b, Rgs9), and photoreceptor disc morphogenesis (Rpgrip1 and Fscn2). Levels of RPE65 were significantly decreased by 2.0-fold. Transcripts of Prss56, a gene associated with angle-closure glaucoma, posterior microphthalmia and myopia, were increased in Mfrprd6 eyes by 17-fold. Validation by qRT-PCR indicated a 3.5-, 14- and 70-fold accumulation of Prss56 transcripts relative to controls at P7, P14 and P21, respectively. This trend was not observed in other RPE or photoreceptor mutant mouse models with similar disease progression, suggesting that Prss56 upregulation is a specific attribute of the disruption of Mfrp. Prss56 and Glul in situ hybridization directly identified Müller glia in the inner nuclear layer as the cell type expressing Prss56. In summary, the Mfrprd6 allele causes significant postnatal changes in transcript and protein levels in the retina and RPE. The link between Mfrp deficiency and Prss56 up-regulation, together with the genetic association of human MFRP or PRSS56 variants and ocular size, raises the possibility that these genes are part of a regulatory network influencing postnatal posterior eye development.
- Published
- 2014
- Full Text
- View/download PDF
16. Meckelin is necessary for photoreceptor intraciliary transport and outer segment morphogenesis.
- Author
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Collin GB, Won J, Hicks WL, Cook SA, Nishina PM, and Naggert JK
- Subjects
- Animals, Cilia genetics, Cilia metabolism, Cilia ultrastructure, Ciliary Motility Disorders metabolism, Ciliary Motility Disorders pathology, Disease Models, Animal, Encephalocele metabolism, Encephalocele pathology, Genotype, Immunohistochemistry, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Polycystic Kidney Diseases metabolism, Polycystic Kidney Diseases pathology, Polymerase Chain Reaction, Protein Transport, Rod Cell Outer Segment ultrastructure, Ciliary Motility Disorders genetics, DNA genetics, Encephalocele genetics, Membrane Proteins genetics, Morphogenesis drug effects, Mutation, Polycystic Kidney Diseases genetics, Rod Cell Outer Segment physiology
- Abstract
Purpose: Cilia, complex structures found ubiquitously in most vertebrate cells, serve a variety of functions ranging from cell and fluid movement, cell signaling, tissue homeostasis, to sensory perception. Meckelin is a component of ciliary and cell membranes and is encoded by Tmem67 (Mks3). In this study, the retinal morphology and ciliary function in a mouse model for Meckel Syndrome Type 3 (MKS3) throughout the course of photoreceptor development was examined., Methods: To study the effects of a disruption in the Mks3 gene on the retina, the authors introduced a functional allele of Pde6b into B6C3Fe a/a-bpck/J mice and evaluated their retinas by ophthalmoscopic, histologic, and ultrastructural examination. In addition, immunofluorescence microscopy was used to assess protein trafficking through the connecting cilium and to examine the localization of ciliary and synaptic proteins in Tmem67(bpck) mice and controls., Results: Photoreceptors degenerate early and rapidly in bpck/bpck mutant mice. In addition, phototransduction proteins, such as rhodopsin, arrestin, and transducin, are mislocalized. Ultrastructural examination of photoreceptors reveal morphologically intact connecting cilia but dysmorphic and misoriented outer segment (OS) discs, at the earliest time point examined., Conclusions: These findings underscore the important role for meckelin in intraciliary transport of phototransduction molecules and their effects on subsequent OS morphogenesis and maintenance.
- Published
- 2012
- Full Text
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17. An ENU-induced mutation in the Mertk gene (Mertknmf12) leads to a slow form of retinal degeneration.
- Author
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Maddox DM, Hicks WL, Vollrath D, LaVail MM, Naggert JK, and Nishina PM
- Subjects
- Animals, Blotting, Western, Cell Death drug effects, Cell Death genetics, Disease Models, Animal, Disease Progression, Electroretinography, Immunohistochemistry, Mice, Mice, Inbred C57BL, Ophthalmoscopy, Phenotype, Photoreceptor Cells, Vertebrate drug effects, Photoreceptor Cells, Vertebrate metabolism, Photoreceptor Cells, Vertebrate pathology, Proto-Oncogene Proteins biosynthesis, Receptor Protein-Tyrosine Kinases biosynthesis, Retina drug effects, Retina pathology, Retinal Degeneration pathology, Retinal Degeneration physiopathology, Tumor Necrosis Factor-alpha biosynthesis, c-Mer Tyrosine Kinase, DNA genetics, Ethylnitrosourea toxicity, Mutation drug effects, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases genetics, Retina metabolism, Retinal Degeneration genetics
- Abstract
Purpose: To determine the basis and to characterize the phenotype of a chemically induced mutation in a mouse model of retinal degeneration., Methods: Screening by indirect ophthalmoscopy identified a line of N-ethyl-N-nitrosourea (ENU) mutagenized mice demonstrating retinal patches. Longitudinal studies of retinal histologic sections showed photoreceptors in the peripheral retina undergoing slow, progressive degeneration. The mutation was named neuroscience mutagenesis facility 12 (nmf12), and mapping localized the critical region to Chromosome 2., Results: Sequencing of nmf12 DNA revealed a point mutation in the c-mer tyrosine kinase gene, designated Mertk(nmf12). We detected elevated levels of tumor necrosis factor (Tnf, previously Tnfa) in retinas of Mertk(nmf12) homozygotes relative to wild-type controls and investigated whether the increase of TNF, an inflammatory cytokine produced by macrophages/monocytes that signals intracellularly to cause necrosis or apoptosis, could underlie the retinal degeneration observed in Mertk(nmf12) homozygotes. Mertk(nmf12) homozygous mice were mated to mice lacking the entire Tnf gene and partial coding sequences of the Lta (Tnfb) and Ltb (Tnfc) genes.(2) B6.129P2-Ltb/Tnf/Lta(tm1Dvk)/J homozygotes did not exhibit a retinal degeneration phenotype and will, hereafter, be referred to as Tnfabc(-/-) mice. Surprisingly, mice homozygous for both the Mertk(nmf12) and the Ltb/Tnf/Lta(tm1Dvk) allele (Tnfabc(-/-)) demonstrated an increase in the rate of retinal degeneration., Conclusions: These findings illustrate that a mutation in the Mertk gene leads to a significantly slower progressive retinal degeneration compared with other alleles of Mertk. These results demonstrate that TNF family members play a role in protecting photoreceptors of Mertk(nmf12) homozygotes from cell death.
- Published
- 2011
- Full Text
- View/download PDF
18. Photoreceptor degeneration, azoospermia, leukoencephalopathy, and abnormal RPE cell function in mice expressing an early stop mutation in CLCN2.
- Author
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Edwards MM, Marín de Evsikova C, Collin GB, Gifford E, Wu J, Hicks WL, Whiting C, Varvel NH, Maphis N, Lamb BT, Naggert JK, Nishina PM, and Peachey NS
- Subjects
- Animals, Azoospermia pathology, Blotting, Western, Brain pathology, CLC-2 Chloride Channels, Electroretinography, Ethylnitrosourea toxicity, Female, Genome-Wide Association Study, Leukoencephalopathies pathology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mutagenesis drug effects, Retinal Degeneration pathology, Azoospermia genetics, Chloride Channels genetics, Codon, Nonsense, Leukoencephalopathies genetics, Photoreceptor Cells, Vertebrate pathology, Retinal Degeneration genetics, Retinal Pigment Epithelium pathology
- Abstract
Purpose: To determine the molecular basis and the pathologic consequences of a chemically induced mutation in a mouse model of photoreceptor degeneration, nmf240., Methods: Mice from a G3 N-ethyl-N-nitrosourea mutagenesis program were screened by indirect ophthalmoscopy for abnormal fundi. A chromosomal position for the recessive nmf240 mutation was determined by a genome-wide linkage analysis by use of simple sequence length polymorphic markers in an F2 intercross. The critical region was refined, and candidate genes were screened by direct sequencing. The nmf240 phenotype was characterized by histologic analysis of the retina, brain, and male reproductive organs and by electroretinogram (ERG)-based studies of the retina and retinal pigment epithelium (RPE)., Results: Clinically, homozygous nmf240 mutants exhibit a grainy retina that progresses to panretinal patches of depigmentation. The mutation was localized to a region on chromosome 16 containing Clcn2, a gene associated with retinal degeneration. Sequencing identified a missense C-T mutation at nucleotide 1063 in Clcn2 that converts a glutamine to a stop codon. Mice homozygous for the Clcn2(nmf240) mutation experience a severe loss of photoreceptor cells at 14 days of age that is preceded by an elongation of RPE apical microvilli. Homozygous mutants also experience leukoencephalopathy in multiple brain areas and male sterility. Despite a normal retinal histology in nmf240 heterozygotes, the ERG light peak, generated by the RPE, is reduced., Conclusions: The nmf240 phenotype closely resembles that reported for Clcn2 knockout mice. The observation that heterozygous nmf240 mice present with a reduced ERG light peak component suggests that CLCN2 is necessary for the generation of this response component.
- Published
- 2010
- Full Text
- View/download PDF
19. Membrane frizzled-related protein is necessary for the normal development and maintenance of photoreceptor outer segments.
- Author
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Won J, Smith RS, Peachey NS, Wu J, Hicks WL, Naggert JK, and Nishina PM
- Subjects
- Aging metabolism, Animals, Animals, Newborn, Down-Regulation, Electroretinography, Embryo, Mammalian metabolism, Embryonic Development, Eye Proteins genetics, Eye Proteins metabolism, Gene Deletion, Gene Expression, Light, Membrane Proteins deficiency, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Phagocytosis radiation effects, Photoreceptor Cells pathology, Pigment Epithelium of Eye pathology, Retina physiopathology, Retina ultrastructure, Retinal Rod Photoreceptor Cells pathology, Tissue Distribution, Eye Proteins physiology, Membrane Proteins physiology, Photoreceptor Cells physiology
- Abstract
A 4 base pair deletion in a splice donor site of the Mfrp (membrane-type frizzled-related protein) gene, herein referred to as Mfrprd6/rd6, is predicted to lead to the skipping of exon 4 and photoreceptor degeneration in retinal degeneration 6 (rd6) mutant mice. Little, however, is known about the function of the protein or how the mutation causes the degenerative retinal phenotype. Here we examine ultrastructural changes in the retina of Mfrprd6/rd6 mice to determine the earliest effects of the mutation. We also extend the reported observations of the expression pattern of the dicistronic Mfrp/C1qtnf5 message and the localization of these and other retinal pigment epithelium (RPE) and retinal proteins during development and assess the ability of RPE cells to phagocytize outer segments (OSs) in mutant and wild-type (WT) mice. At the ultrastructural level, OSs do not develop normally in Mfrprd6/rd6 mutants. They are disorganized and become progressively shorter as mutant mice age. Additionally, there are focal areas in which there is a reduction of apical RPE microvilli. At P25, the rod electroretinogram (ERG) a-wave of Mfrprd6/rd6 mice is reduced in amplitude by ~50% as are ERG components generated by the RPE. Examination of beta-catenin localization and Fos and Tcf-1 expression, intermediates of the canonical Wnt pathway, showed that they were not different between mutant and WT mice, suggesting that MFRP may operate through an alternative pathway. Finally, impaired OS phagocytosis was observed in Mfrprd6/rd6 mice both in standard ambient lighting conditions and with bright light exposure when compared to WT controls.
- Published
- 2008
- Full Text
- View/download PDF
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