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The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum

The Moonwalker (Mwk) mouse is a model of dominantly inherited cerebellar ataxia caused by a gain-of-function mutation in the transient receptor potential (TRP) channel TRPC3. Here, we report impairments in dendritic growth and synapse formation early on during Purkinje cell development in the Mwk ce...

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Autores principales: Dulneva, Anna, Lee, Sheena, Oliver, Peter L., Di Gleria, Katalin, Kessler, Benedikt M., Davies, Kay E., Becker, Esther B. E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476454/
https://www.ncbi.nlm.nih.gov/pubmed/25908616
http://dx.doi.org/10.1093/hmg/ddv150
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author Dulneva, Anna
Lee, Sheena
Oliver, Peter L.
Di Gleria, Katalin
Kessler, Benedikt M.
Davies, Kay E.
Becker, Esther B. E.
author_facet Dulneva, Anna
Lee, Sheena
Oliver, Peter L.
Di Gleria, Katalin
Kessler, Benedikt M.
Davies, Kay E.
Becker, Esther B. E.
author_sort Dulneva, Anna
collection PubMed
description The Moonwalker (Mwk) mouse is a model of dominantly inherited cerebellar ataxia caused by a gain-of-function mutation in the transient receptor potential (TRP) channel TRPC3. Here, we report impairments in dendritic growth and synapse formation early on during Purkinje cell development in the Mwk cerebellum that are accompanied by alterations in calcium signaling. To elucidate the molecular effector pathways that regulate Purkinje cell dendritic arborization downstream of mutant TRPC3, we employed transcriptomic analysis of developing Purkinje cells isolated by laser-capture microdissection. We identified significant gene and protein expression changes in molecules involved in lipid metabolism. Consistently, lipid homeostasis in the Mwk cerebellum was found to be disturbed, and treatment of organotypic cerebellar slices with ceramide significantly improved dendritic outgrowth of Mwk Purkinje cells. These findings provide the first mechanistic insights into the TRPC3-dependent mechanisms, by which activated calcium signaling is coupled to lipid metabolism and the regulation of Purkinje cell development in the Mwk cerebellum.
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spelling pubmed-44764542015-06-24 The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum Dulneva, Anna Lee, Sheena Oliver, Peter L. Di Gleria, Katalin Kessler, Benedikt M. Davies, Kay E. Becker, Esther B. E. Hum Mol Genet Articles The Moonwalker (Mwk) mouse is a model of dominantly inherited cerebellar ataxia caused by a gain-of-function mutation in the transient receptor potential (TRP) channel TRPC3. Here, we report impairments in dendritic growth and synapse formation early on during Purkinje cell development in the Mwk cerebellum that are accompanied by alterations in calcium signaling. To elucidate the molecular effector pathways that regulate Purkinje cell dendritic arborization downstream of mutant TRPC3, we employed transcriptomic analysis of developing Purkinje cells isolated by laser-capture microdissection. We identified significant gene and protein expression changes in molecules involved in lipid metabolism. Consistently, lipid homeostasis in the Mwk cerebellum was found to be disturbed, and treatment of organotypic cerebellar slices with ceramide significantly improved dendritic outgrowth of Mwk Purkinje cells. These findings provide the first mechanistic insights into the TRPC3-dependent mechanisms, by which activated calcium signaling is coupled to lipid metabolism and the regulation of Purkinje cell development in the Mwk cerebellum. Oxford University Press 2015-07-15 2015-04-23 /pmc/articles/PMC4476454/ /pubmed/25908616 http://dx.doi.org/10.1093/hmg/ddv150 Text en © The Author 2015. Published by Oxford University Press http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Dulneva, Anna
Lee, Sheena
Oliver, Peter L.
Di Gleria, Katalin
Kessler, Benedikt M.
Davies, Kay E.
Becker, Esther B. E.
The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum
title The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum
title_full The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum
title_fullStr The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum
title_full_unstemmed The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum
title_short The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum
title_sort mutant moonwalker trpc3 channel links calcium signaling to lipid metabolism in the developing cerebellum
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476454/
https://www.ncbi.nlm.nih.gov/pubmed/25908616
http://dx.doi.org/10.1093/hmg/ddv150
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