Analysis of the roles of POMGnT1 in development and maintenance of certral nervous system and skeletal muscle
| Project/Area Number |
18590392
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | National Center of Neurology and Psychiatry |
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Principal Investigator |
SUZUKI Yuko National Center of Neurology and Psychiatry, Natioanl Institute of Neuroscience, Department of Molecular Therapy, Section Chief (00342931)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEDA Shinichi National Institute of Neuroscience, Department of Molecular Therapy, Director (90171644)
ENDO Tamao Tokyo Metropolitan Institute of Gerontology, Foundation for Research on Aging and Promotion of Human Welfare, Glycobiology Research Group, Director (30168827)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | glycosylation / POMGnT1 / alpha-dystroglycan / skeletal muscle / muscle satallite cells / muscle-eye-brain disease / laminin / neuronal migration |
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| Research Abstract |
Protein O-linked mannose β1, 2-N-acetylglucosaminyltransferase 1(POMGnT1) is an enzyme that transfers N-acetylglucosamine to O-mannose of glycoproteins, and is indispensable for (O-mannosyl glycosylation of alpha-dystroglycan(α-DG), a component of the dystrophin-glycoprotein complex. Mutation of the POMGnT1 gene is a cause of muscle-eye-brain(MEB) disease, which is characterized by severe congenital muscular dystrophy and abnormalities of the eyes and central nervous system(CNS). To obtain a better understanding of the pathogenesis of MEB disease, we mutated the POMGnT1 gene in mice using a targeting technique.
1) Skeletal muscle The mutant muscle showed aberrant glycosylation of α-DG and α-DG from mutant muscle failed to bind laminin in a binding assay. POMGnT1^<-/-> muscle showed minimal pathological changes with very low serum creatinine kinase levels, and had normally formed muscle basal lamina. Importantly, POMGnT1^<-/-> satellite cells proliferated slowly, but efficiently differen
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tiated into multinuclear myotubes in vitro. Transfer of a retrovirus vector-mediated POMGnT1 gene into POMGnT1^<-/-> myoblasts completely restored the glycosylation of α-DG, but proliferation of the cells was not improved. Our results suggest that α-DG is not directly involved in the proliferation and differentiation of myoblasts but that its glycosylation is important for maintenance of the proliferative capacity of satellite cells in the postnatal stage.
2) CNS The cerebral cortex of POMGnT1^<-/-> mice showed abnormal migration of neurons, disrupted glia limitans and reactive gliosis. The expression of reelin was widely up-regulated in the mutant neocortex. We tested whether the restoration of POMGnT1 expression in neuron results in normal migration along the radial glia. To this end, we electroporated a POMGnT1-expressing plasmid into the ventricular zone of E12 and E15 embryos in utero.
Surprisingly, the migration pattern of POMGnT1-deficient neuron did not change after restoration of POMGnT1 expression. The results suggest that the abnormal migration of POMGnT1^<-/-> neurons is not due to deficiency ogf POMGn1 activity in neuron but likely due to abnormality of radial glial cells(Bergmann glia), which have long radial processes extending from the ventricular zone(VZ) to the pial surface and serve a railroad of neuronal migration. Less
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Report
(3 results)
Research Products
(37 results)
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[Journal Article] CD90-positive cells, an additional cell population, produce laminin alpha2 upon transplantation to dy(3k)/dy(3k) mice2008
Author(s)
Fukada S, Yamamoto Y, Segawa M, Sakamoto K, Nakajima M, Sato M, Morikawa D, Uezumi A, Miyagoe-Suzuki Y, Takeda S, Tsujikawa K, Yamamoto H.
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Journal Title
Experimental Cell Research 314
Pages: 193-203
Description
「研究成果報告書概要(和文)」より
Related Report
Peer Reviewed
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[Journal Article] CD90-positive cells, an additional cell population, produce laminin alpha2 upon transplantation to dy(3k) /dy(3k) mice2008
Author(s)
Fukada S, Yamamoto Y, Segawa M, Sakamoto K, Nakajima M, Sato M, Morikawa D, Uezumi A, Miyagoe-Suzuki Y, Takeda S, Tsujikawa K, Yamamoto H
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Journal Title
Experimental Cell Research 314
Pages: 193-203
Description
「研究成果報告書概要(欧文)」より
Related Report
-
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[Journal Article] CD90-positive cells.an additional cell population, produce laminin alpha2 upon transplantation to dy(3k)/dyd3k)mice2008
Author(s)
Fukada S, Yamamoto Y, Segawa M, Sakamoto K, Nakajima M, Sato M, Morikawa D, Uezumi A, Miyagoe-Suzuki Y, Takeda S, Tsuiikawa K, Yamamoto H.
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Journal Title
Experimental Cell Research 314
Pages: 193-203
Related Report
Peer Reviewed
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[Presentation] HDAC11 regulates differentiation of satellite cells.2007
Author(s)
Erica Yada, Norio Motohashi, Makoto Miyagishi, Chika Harano, Yuko Miyagoe-Suzuki, Shin'ichi Takeda.
Organizer
FASEB summer research conference, skeletal muscle satellite cells & stem cells
Place of Presentation
Indian Wells, California
Description
「研究成果報告書概要(和文)」より
Related Report
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[Presentation] HDAC11 regulates differentiation of satellite cells.2007
Author(s)
Erica Yada, Norio Motohashi, Makoto Miyagishi, Chika Harano, Yuko Miyagoe-Suzuki, Shin'ichi Takeda
Organizer
FASEB summer research coference, skeletal muscle satellite cells & stem cells.
Place of Presentation
Indian Wells, California
Description
「研究成果報告書概要(欧文)」より
Related Report
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