title: The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum.
abstract: 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.
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK and.
authors.forename: Anna
authors.initials: A
authors.lastname: Dulneva
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK and.
authors.forename: Sheena
authors.initials: S
authors.lastname: Lee
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK and.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
authors.affiliation: TDI Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Katalin
authors.initials: K
authors.lastname: Di Gleria
authors.affiliation: TDI Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK and kay.davies@dpag.ox.ac.uk esther.becker@dpag.ox.ac.uk.
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK and kay.davies@dpag.ox.ac.uk esther.becker@dpag.ox.ac.uk.
authors.forename: Esther B E
authors.initials: EB
authors.lastname: Becker
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism / Q000502:physiology*; D003712:Dendrites / Q000378:metabolism; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D051379:Mice; D011689:Purkinje Cells / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D050052:TRPC Cation Channels; C104603:TRPC3 cation channel