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[PMID]:28744553
[Au] Autor:Sakagami H; Katsumata O; Hara Y; Sasaoka T; Fukaya M
[Ad] Endereço:Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
[Ti] Título:BRAG2a, a Guanine Nucleotide Exchange Factor for Arf6, Is a Component of the Dystrophin-Associated Glycoprotein Complex at the Photoreceptor Terminal.
[So] Source:Invest Ophthalmol Vis Sci;58(9):3795-3803, 2017 07 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Mutations in genes encoding the dystrophin-associated glycoprotein complex (DGC) can cause muscular dystrophy and disturb synaptic transmission in the photoreceptor ribbon synapse. However, the molecular composition and specific functions of the photoreceptor DGC remain unknown. Brefeldin A-resistant Arf-GEF 2 (BRAG2), also known as IQSEC1, is a guanine nucleotide exchange factor for ADP-ribosylation factor 6 (Arf6), a critical GTPase that regulates endosomal trafficking and actin cytoskeleton remodeling. In the present study, we characterized the expression of BRAG2a, an alternative splicing isoform of BRAG2, in the adult mouse photoreceptor. Methods: Immunofluorescence and immunoelectron microscopic analyses of adult mouse retinas were performed using a novel anti-BRAG2a antibody. Pull-down, immunoprecipitation, and in situ proximity ligation assays were performed to examine the interaction between BRAG2a and the DGC in vivo. Results: Immunofluorescence demonstrated punctate colocalization of BRAG2a with ß-dystroglycan in the outer plexiform layer. Immunoelectron microscopy revealed the localization of BRAG2a at the plasma membrane of lateral walls and processes of photoreceptor terminals within the synaptic cavity. Pull-down and immunoprecipitation assays using retinal lysates demonstrated the protein complex formation between BRAG2a with the DGC. In situ proximity ligation assays further detected a close spatial relationship between BRAG2a and ß-dystroglycan in the outer plexiform layer. Conclusions: The present study provided evidence that BRAG2a is a novel component of the photoreceptor DGC, suggesting functional involvement of the BRAG2a-Arf6 pathway downstream of the DGC.
[Mh] Termos MeSH primário: Fatores de Ribosilação do ADP/metabolismo
Distroglicanas/metabolismo
Complexo de Proteínas Associadas Distrofina/metabolismo
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Células Fotorreceptoras de Vertebrados/metabolismo
Terminações Pré-Sinápticas/metabolismo
[Mh] Termos MeSH secundário: Processamento Alternativo
Animais
Técnica Indireta de Fluorescência para Anticorpo
Immunoblotting
Hibridização In Situ
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Microscopia Confocal
Microscopia Imunoeletrônica
Plasmídeos
Reação em Cadeia da Polimerase
Isoformas de Proteínas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Dystrophin-Associated Protein Complex); 0 (Guanine Nucleotide Exchange Factors); 0 (Iqsec1 protein, mouse); 0 (Protein Isoforms); 146888-27-9 (Dystroglycans); EC 3.6.5.2 (ADP-Ribosylation Factors); EC 3.6.5.2 (ADP-ribosylation factor 6)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-21746


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[PMID]:29320543
[Au] Autor:Blaeser A; Awano H; Lu P; Lu QL
[Ad] Endereço:McColl-Lockwood Laboratory for Muscular Dystrophy Research, Carolinas HealthCare System, Charlotte, North Carolina, United States of America.
[Ti] Título:Distinct expression of functionally glycosylated alpha-dystroglycan in muscle and non-muscle tissues of FKRP mutant mice.
[So] Source:PLoS One;13(1):e0191016, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The glycosylation of alpha-dystroglycan (α-DG) is crucial in maintaining muscle cell membrane integrity. Dystroglycanopathies are identified by the loss of this glycosylation leading to a breakdown of muscle cell membrane integrity and eventual degeneration. However, a small portion of fibers expressing functionally glycosylated α-DG (F-α-DG) (revertant fibers, RF) have been identified. These fibers are generally small in size, centrally nucleated and linked to regenerating fibers. Examination of different muscles have shown various levels of RFs but it is unclear the extent of which they are present. Here we do a body-wide examination of muscles from the FKRP-P448L mutant mouse for the prevalence of RFs. We have identified great variation in the distribution of RF in different muscles and tissues. Triceps shows a large increase in RFs and together with centrally nucleated fibers whereas the pectoralis shows a reduction in revertant but increase in centrally nucleated fibers from 6 weeks to 6 months of age. We have also identified that the sciatic nerve with near normal levels of F-α-DG in the P448Lneo- mouse with reduced levels in the P448Lneo+ and absent in LARGEmyd. The salivary gland of LARGEmyd mice expresses high levels of F-α-DG. Interestingly the same glands in the P448Lneo-and to a lesser degree in P448Lneo+ also maintain considerable amount of F-α-DG, indicating the non-proliferating epithelial cells have a molecular setting permitting glycosylation.
[Mh] Termos MeSH primário: Distroglicanas/metabolismo
Músculo Esquelético/metabolismo
Mutação
N-Acetilglucosaminiltransferases/fisiologia
Nervos Periféricos/metabolismo
Proteínas/fisiologia
Glândulas Salivares/metabolismo
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Distroglicanas/genética
Glicosilação
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Fibras Musculares Esqueléticas/metabolismo
Fibras Musculares Esqueléticas/patologia
Músculo Esquelético/patologia
Nervos Periféricos/patologia
Regeneração/fisiologia
Glândulas Salivares/patologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Dag1 protein, mouse); 0 (Fkrp protein, mouse); 0 (Proteins); 146888-27-9 (Dystroglycans); EC 2.4.1.- (Large protein, mouse); EC 2.4.1.- (N-Acetylglucosaminyltransferases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191016


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[PMID]:28458505
[Au] Autor:Wang E; Geng A; Seo R; Maniar A; Gong X
[Ad] Endereço:School of Optometry and Vision Science Program, University of California, Berkeley, Berkeley, CA.
[Ti] Título:Knock-in of Cx46 partially rescues fiber defects in lenses lacking Cx50.
[So] Source:Mol Vis;23:160-170, 2017.
[Is] ISSN:1090-0535
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Connexins 46 (Cx46) and 50 (Cx50) support lens development and homeostasis. Knockout (KO) of Cx50, but not Cx46, causes defects in lens fiber organization, F-actin enrichment, gap junction (GJ) size, ball-and-socket (BS) maturation, and GJ-associated protein distributions. To further determine the unique roles of Cx50 and Cx46, we investigated whether these defects persisted in Cx46 knock-in (Ki) lenses. Ki mice had Cx46 knocked-in to their Cx50 loci, where it was expressed under endogenous Cx50 promoters. METHODS: Fiber cell morphology and the distribution of lens membrane/cytoskeleton proteins from wild-type (WT), Ki, and Cx50 KO mice were visualized by immunofluorescent labeling and confocal microscopy. RESULTS: Cx46 Ki partially rescued Cx50 KO lens fiber defects. Three-week-old Ki lens fibers had typical F-actin distributions but were nonuniformly sized and disorganized. The Cx-associated proteins zonula occludens-1 (ZO-1) and ß-dystroglycan (ßDys) no longer localized to the nuclei but remained absent from GJs. BS formed, but this occurred with lower than WT frequency. BS appeared with greater frequency in 8-week-old Ki lenses, but so did aberrant balloon-like structures similar to those in Cx50 KO lenses. Unexpectedly, 8-week-old Cx50 KO and Ki cortical lens fibers were no longer disorganized. CONCLUSIONS: Cx identity is important for some aspects of fiber development (organization, Cx association with ZO-1 and ßDys) but not others (F-actin enrichment). Either Cx supports BS maturation, but the sparsity of BS and presence of balloon-like structures in Ki lenses suggest that Cx50 is more capable of doing so. The partial rescue of BS structures may support the rapid growth of cortical fibers to the improved growth of Ki lenses compared to Cx50 KO lenses at young ages. Neither absence of Cx50 nor presence of Ki Cx46 affects cortical fiber cell organization by the age of 8 weeks.
[Mh] Termos MeSH primário: Conexinas/genética
Conexinas/fisiologia
Cristalinas/fisiologia
Técnicas de Introdução de Genes
Técnicas de Inativação de Genes
Cristalino/citologia
[Mh] Termos MeSH secundário: Actinas/metabolismo
Envelhecimento/fisiologia
Animais
Citoesqueleto/metabolismo
Distroglicanas/metabolismo
Técnica Indireta de Fluorescência para Anticorpo
Junções Comunicantes/metabolismo
Cristalino/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Microscopia Confocal
Proteína da Zônula de Oclusão-1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Connexins); 0 (Crystallins); 0 (Tjp1 protein, mouse); 0 (Zonula Occludens-1 Protein); 0 (connexin 46); 0 (connexin 50); 146888-27-9 (Dystroglycans)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:29221435
[Au] Autor:König E; Volpato CB; Motta BM; Blankenburg H; Picard A; Pramstaller P; Casella M; Rauhe W; Pompilio G; Meraviglia V; Domingues FS; Sommariva E; Rossini A
[Ad] Endereço:Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.
[Ti] Título:Exploring digenic inheritance in arrhythmogenic cardiomyopathy.
[So] Source:BMC Med Genet;18(1):145, 2017 12 08.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder, characterized by the substitution of heart muscle with fibro-fatty tissue and severe ventricular arrhythmias, often leading to heart failure and sudden cardiac death. ACM is considered a monogenic disorder, but the low penetrance of mutations identified in patients suggests the involvement of additional genetic or environmental factors. METHODS: We used whole exome sequencing to investigate digenic inheritance in two ACM families where previous diagnostic tests have revealed a PKP2 mutation in all affected and some healthy individuals. In family members with PKP2 mutations we determined all genes that harbor variants in affected but not in healthy carriers or vice versa. We computationally prioritized the most likely candidates, focusing on known ACM genes and genes related to PKP2 through protein interactions, functional relationships, or shared biological processes. RESULTS: We identified four candidate genes in family 1, namely DAG1, DAB2IP, CTBP2 and TCF25, and eleven candidate genes in family 2. The most promising gene in the second family is TTN, a gene previously associated with ACM, in which the affected individual harbors two rare deleterious-predicted missense variants, one of which is located in the protein's only serine kinase domain. CONCLUSIONS: In this study we report genes that might act as digenic players in ACM pathogenesis, on the basis of co-segregation with PKP2 mutations. Validation in larger cohorts is still required to prove the utility of this model.
[Mh] Termos MeSH primário: Displasia Arritmogênica Ventricular Direita/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Oxirredutases do Álcool/genética
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Conectina/química
Conectina/genética
Distroglicanas/genética
Feminino
Seres Humanos
Masculino
Meia-Idade
Modelos Moleculares
Mutação
Proteínas do Tecido Nervoso/genética
Linhagem
Placofilinas/genética
Domínios Proteicos
Proteínas Repressoras/genética
Sequenciamento Completo do Exoma
Proteínas Ativadoras de ras GTPase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Connectin); 0 (DAB2IP protein, human); 0 (DAG1 protein, human); 0 (Nerve Tissue Proteins); 0 (PKP2 protein, human); 0 (Plakophilins); 0 (Repressor Proteins); 0 (TCF25 protein, human); 0 (TTN protein, human); 0 (ras GTPase-Activating Proteins); 146888-27-9 (Dystroglycans); EC 1.1.- (Alcohol Oxidoreductases); EC 1.1.- (CTBP2 protein, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171231
[Lr] Data última revisão:
171231
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171210
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0503-7


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[PMID]:29044412
[Au] Autor:Kálmán M; Tóth L; Szöllosi D; Oszwald E; Mahalek J; Sadeghian S
[Ad] Endereço:Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary.
[Ti] Título:Correlation Between Extravasation and Alterations of Cerebrovascular Laminin and ß-Dystroglycan Immunoreactivity Following Cryogenic Lesions in Rats.
[So] Source:J Neuropathol Exp Neurol;76(11):929-941, 2017 Nov 01.
[Is] ISSN:1554-6578
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The blood-brain barrier becomes "leaky" following lesions. Former studies revealed that following lesions the immunoreactivity of cerebrovascular laminin becomes detectable whereas that of ß-dystroglycan disappears. These alterations may be indicators of glio-vascular decoupling that may result in the impairment of the blood-brain-barrier. This study investigates correlation between the post-lesion extravasation and the above-mentioned immunohistochemical alterations. Following cryogenic lesions, the survival periods lasted 5, 10, 30 minutes, 1 or 12 hours, or 1 day. Some brains were fixed immediately post-lesion. Immunofluorescent reactions were performed in floating sections. The extravasation was detected with immunostaining for plasma fibronectin and rat immunoglobulins. When the survival period was 30 minutes or longer, the area of extravasation corresponded to the area of altered laminin and ß-dystroglycan immunoreactivities. Following immediate fixation some laminin immunoreactivity was already detected. The extravasation seemed to precede this early appearance of laminin immunoreactivity. The ß-dystroglycan immunoreactivity disappeared later. When the extravasation spread into the corpus callosum, vascular laminin immunoreactivity appeared but the ß-dystroglycan immunoreactivity persisted. It seems that extravasation separates the glial and vascular basal laminae, which results in the appearance of laminin immunoreactivity. The disappearance of ß-dystroglycan immunoreactivity is neither a condition nor an inevitable consequence of the 2 other phenomena.
[Mh] Termos MeSH primário: Distroglicanas/análise
Extravasamento de Materiais Terapêuticos e Diagnósticos/patologia
Congelamento/efeitos adversos
Laminina/análise
Lobo Parietal/química
Lobo Parietal/patologia
[Mh] Termos MeSH secundário: Animais
Barreira Hematoencefálica/química
Barreira Hematoencefálica/patologia
Circulação Cerebrovascular/fisiologia
Feminino
Masculino
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Laminin); 146888-27-9 (Dystroglycans)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171019
[St] Status:MEDLINE
[do] DOI:10.1093/jnen/nlx081


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[PMID]:29036200
[Au] Autor:Covaceuszach S; Bozzi M; Bigotti MG; Sciandra F; Konarev PV; Brancaccio A; Cassetta A
[Ad] Endereço:Istituto di Cristallografia-CNR, Trieste Outstation, Trieste, Italy.
[Ti] Título:The effect of the pathological V72I, D109N and T190M missense mutations on the molecular structure of α-dystroglycan.
[So] Source:PLoS One;12(10):e0186110, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dystroglycan (DG) is a highly glycosylated protein complex that links the cytoskeleton with the extracellular matrix, mediating fundamental physiological functions such as mechanical stability of tissues, matrix organization and cell polarity. A crucial role in the glycosylation of the DG α subunit is played by its own N-terminal region that is required by the glycosyltransferase LARGE. Alteration in this O-glycosylation deeply impairs the high affinity binding to other extracellular matrix proteins such as laminins. Recently, three missense mutations in the gene encoding DG, mapped in the α-DG N-terminal region, were found to be responsible for hypoglycosylated states, causing congenital diseases of different severity referred as primary dystroglycanopaties.To gain insight on the molecular basis of these disorders, we investigated the crystallographic and solution structures of these pathological point mutants, namely V72I, D109N and T190M. Small Angle X-ray Scattering analysis reveals that these mutations affect the structures in solution, altering the distribution between compact and more elongated conformations. These results, supported by biochemical and biophysical assays, point to an altered structural flexibility of the mutant α-DG N-terminal region that may have repercussions on its interaction with LARGE and/or other DG-modifying enzymes, eventually reducing their catalytic efficiency.
[Mh] Termos MeSH primário: Distroglicanas/química
Distroglicanas/genética
Mutação de Sentido Incorreto
[Mh] Termos MeSH secundário: Animais
Cristalografia
Distroglicanas/metabolismo
Estabilidade Enzimática
Fluorometria
Camundongos
Modelos Moleculares
Mutagênese Sítio-Dirigida
Desnaturação Proteica
Espalhamento a Baixo Ângulo
Soluções
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Solutions); 146888-27-9 (Dystroglycans)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186110


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[PMID]:28821434
[Au] Autor:Fukai Y; Ohsawa Y; Ohtsubo H; Nishimatsu SI; Hagiwara H; Noda M; Sasaoka T; Murakami T; Sunada Y
[Ad] Endereço:Department of Neurology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan.
[Ti] Título:Cleavage of ß-dystroglycan occurs in sarcoglycan-deficient skeletal muscle without MMP-2 and MMP-9.
[So] Source:Biochem Biophys Res Commun;492(2):199-205, 2017 Oct 14.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The dystroglycan complex consists of two subunits: extracellular α-dystroglycan and membrane-spanning ß-dystroglycan, which provide a tight link between the extracellular matrix and the intracellular cytoskeleton. Previous studies showed that 43 kDa ß-dystroglycan is proteolytically cleaved into the 30 kDa fragment by matrix metalloproteinases (MMPs) in various non-muscle tissues, whereas it is protected from cleavage in muscles by the sarcoglycan complex which resides close to the dystroglycan complex. It is noteworthy that cleaved ß-dystroglycan is detected in muscles from patients with sarcoglycanopathy, sarcoglycan-deficient muscular dystrophy. In vitro assays using protease inhibitors suggest that both MMP-2 and MMP-9 contribute to the cleavage of ß-dystroglycan. However, this has remained uninvestigated in vivo. METHODS: We generated triple-knockout (TKO) mice targeting MMP-2, MMP-9 and γ-sarcoglycan to examine the status of ß-dystroglycan cleavage in the absence of the candidate matrix metalloproteinases in sarcoglycan-deficient muscles. RESULTS: Unexpectedly, ß-dystroglycan was cleaved in muscles from TKO mice. Muscle pathology was not ameliorated but worsened in TKO mice compared with γ-sarcoglycan single-knockout mice. The gene expression of MMP-14 was up-regulated in TKO mice as well as in γ-sarcoglycan knockout mice. In vitro assay showed MMP-14 is capable to cleave ß-dystroglycan. CONCLUSIONS: Double-targeting of MMP-2 and MMP-9 cannot prevent cleavage of ß-dystroglycan in sarcoglycanopathy. Thus, matrix metalloproteinases contributing to ß-dystroglycan cleavage are redundant, and MMP-14 could participate in the pathogenesis of sarcoglycanopathy.
[Mh] Termos MeSH primário: Distroglicanas/metabolismo
Metaloproteinase 2 da Matriz/genética
Metaloproteinase 9 da Matriz/genética
Músculo Esquelético/metabolismo
Sarcoglicanopatias/genética
Sarcoglicanas/genética
[Mh] Termos MeSH secundário: Animais
Deleção de Genes
Seres Humanos
Metaloproteinase 14 da Matriz/genética
Metaloproteinase 14 da Matriz/metabolismo
Metaloproteinase 2 da Matriz/metabolismo
Metaloproteinase 9 da Matriz/metabolismo
Camundongos Knockout
Músculo Esquelético/patologia
Proteólise
Sarcoglicanopatias/metabolismo
Sarcoglicanopatias/patologia
Sarcoglicanas/metabolismo
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Sarcoglycans); 146888-27-9 (Dystroglycans); EC 3.4.24.24 (Matrix Metalloproteinase 2); EC 3.4.24.35 (Matrix Metalloproteinase 9); EC 3.4.24.80 (Matrix Metalloproteinase 14)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170820
[St] Status:MEDLINE


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[PMID]:28760865
[Au] Autor:Clements R; Turk R; Campbell KP; Wright KM
[Ad] Endereço:Neuroscience Graduate Program and.
[Ti] Título:Dystroglycan Maintains Inner Limiting Membrane Integrity to Coordinate Retinal Development.
[So] Source:J Neurosci;37(35):8559-8574, 2017 Aug 30.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Proper neural circuit formation requires the precise regulation of neuronal migration, axon guidance, and dendritic arborization. Mutations affecting the function of the transmembrane glycoprotein dystroglycan cause a form of congenital muscular dystrophy that is frequently associated with neurodevelopmental abnormalities. Despite its importance in brain development, the role of dystroglycan in regulating retinal development remains poorly understood. Using a mouse model of dystroglycanopathy ( ) and conditional mutants of both sexes, we show that dystroglycan is critical for the proper migration, axon guidance, and dendritic stratification of neurons in the inner retina. Using genetic approaches, we show that dystroglycan functions in neuroepithelial cells as an extracellular scaffold to maintain the integrity of the retinal inner limiting membrane. Surprisingly, despite the profound disruptions in inner retinal circuit formation, spontaneous retinal activity is preserved. These results highlight the importance of dystroglycan in coordinating multiple aspects of retinal development. The extracellular environment plays a critical role in coordinating neuronal migration and neurite outgrowth during neural circuit development. The transmembrane glycoprotein dystroglycan functions as a receptor for multiple extracellular matrix proteins and its dysfunction leads to a form of muscular dystrophy frequently associated with neurodevelopmental defects. Our results demonstrate that dystroglycan is required for maintaining the structural integrity of the inner limiting membrane (ILM) in the developing retina. In the absence of functional dystroglycan, ILM degeneration leads to defective migration, axon guidance, and mosaic spacing of neurons and a loss of multiple neuron types during retinal development. These results demonstrate that disorganization of retinal circuit development is a likely contributor to visual dysfunction in patients with dystroglycanopathy.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Distroglicanas/metabolismo
Células Neuroepiteliais/citologia
Células Neuroepiteliais/fisiologia
Neurogênese/fisiologia
Retina/citologia
Retina/crescimento & desenvolvimento
[Mh] Termos MeSH secundário: Animais
Feminino
Masculino
Camundongos
Camundongos Knockout
Camundongos Transgênicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
146888-27-9 (Dystroglycans)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0946-17.2017


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[PMID]:28687598
[Au] Autor:Sheikh MO; Wells L
[Ad] Endereço:From the Complex Carbohydrate Research Center and.
[Ti] Título:Whoa man! Unexpected protein -mannosylation pathways in mammals.
[So] Source:J Biol Chem;292(27):11599-11600, 2017 Jul 07.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The recent expansion of well-characterized -mannosylated mammalian proteins beyond the archetypical example of α-dystroglycan has inspired new interest in the possibility of additional functional roles of this modification. In an effort to explore those roles, a new study now serendipitously uncovers the existence of an alternative pathway to the well-described POMT (protein -mannosyltransferase) family of -mannosyltransferases.
[Mh] Termos MeSH primário: Distroglicanas/metabolismo
Manosiltransferases/metabolismo
[Mh] Termos MeSH secundário: Animais
Distroglicanas/genética
Glicosilação
Seres Humanos
Manosiltransferases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
146888-27-9 (Dystroglycans); EC 2.4.1.- (Mannosyltransferases); EC 2.4.1.109 (protein O-mannosyltransferase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.H117.794487


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[PMID]:28679759
[Au] Autor:Acciani M; Alston JT; Zhao G; Reynolds H; Ali AM; Xu B; Brindley MA
[Ad] Endereço:Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.
[Ti] Título:Mutational Analysis of Lassa Virus Glycoprotein Highlights Regions Required for Alpha-Dystroglycan Utilization.
[So] Source:J Virol;91(18), 2017 Sep 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lassa virus (LASV) is an enveloped RNA virus endemic to West Africa and responsible for severe cases of hemorrhagic fever. Virus entry is mediated by the glycoprotein complex consisting of a stable-signal peptide, a receptor-binding subunit, GP1, and a viral-host membrane fusion subunit, GP2. Several cellular receptors can interact with the GP1 subunit and mediate viral entry, including alpha-dystroglycan (αDG) and lysosome-associated membrane protein 1 (LAMP1). In order to define the regions within GP1 that interact with the cellular receptors, we implemented insertional mutagenesis, carbohydrate shielding, and alanine scanning mutagenesis. Eighty GP constructs were engineered and evaluated for GP1-GP2 processing, surface expression, and the ability to mediate cell-to-cell fusion after low-pH exposure. To examine virus-to-cell entry, 49 constructs were incorporated onto vesicular stomatitis virus (VSV) pseudoparticles and transduction efficiencies were monitored in HAP1 and HAP1-ΔDAG1 cells that differentially produce the αDG cell surface receptor. Seven constructs retained efficient transduction in HAP1-ΔDAG1 cells yet poorly transduced HAP1 cells, suggesting that they are involved in αDG utilization. Residues H141, N146, F147, and Y150 cluster at the predicted central core of the trimeric interface and are important for GP-αDG interaction. Additionally, H92A-H93A, 150HA, 172HA, and 230HA displayed reduced transduction in both HAP1 and HAP1-ΔDAG1 cells, despite efficient cell-to-cell fusion activity. These mutations may interfere with interactions with the endosomal receptor LAMP1 or interfere at another stage in entry that is common to both cell lines. Insight gained from these data can aid in the development of more-effective entry inhibitors by blocking receptor interactions. Countries in which Lassa virus is endemic, such as Nigeria, Sierra Leone, Guinea, and Liberia, usually experience a seasonal outbreak of the virus from December to March. Currently, there is neither a preventative vaccine nor a therapeutic available to effectively treat severe Lassa fever. One way to thwart virus infection is to inhibit interaction with cellular receptors. It is known that the GP1 subunit of the Lassa glycoprotein complex plays a critical role in receptor recognition. Our results highlight a region within the Lassa virus GP1 protein that interacts with the cellular receptor alpha-dystroglycan. This information may be used for future development of new Lassa virus antivirals.
[Mh] Termos MeSH primário: Distroglicanas/metabolismo
Vírus Lassa/genética
Vírus Lassa/metabolismo
Receptores Virais/metabolismo
Proteínas do Envelope Viral/genética
Proteínas do Envelope Viral/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Análise Mutacional de DNA
Seres Humanos
Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo
Mutagênese Insercional
Mutagênese Sítio-Dirigida
Proteínas Mutantes/genética
Proteínas Mutantes/metabolismo
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Transdução Genética
Vesiculovirus/genética
Vesiculovirus/fisiologia
Internalização do Vírus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (LAMP1 protein, human); 0 (Lysosome-Associated Membrane Glycoproteins); 0 (Mutant Proteins); 0 (Receptors, Virus); 0 (Recombinant Proteins); 0 (Viral Envelope Proteins); 0 (glycoprotein gp1, lassa virus); 146888-27-9 (Dystroglycans)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE



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