title: Inactivation of ceramide synthase 6 in mice results in an altered sphingolipid metabolism and behavioral abnormalities.
abstract: The N-acyl chain length of ceramides is determined by the specificity of different ceramide synthases (CerS). The CerS family in mammals consists of six members with different substrate specificities and expression patterns. We have generated and characterized a mouse line harboring an enzymatically inactive ceramide synthase 6 (CerS6KO) gene and lacz reporter cDNA coding for β-galactosidase directed by the CerS6 promoter. These mice display a decrease in C16:0 containing sphingolipids. Relative to wild type tissues the amount of C16:0 containing sphingomyelin in kidney is ∼35%, whereas we find a reduction of C16:0 ceramide content in the small intestine to about 25%. The CerS6KO mice show behavioral abnormalities including a clasping abnormality of their hind limbs and a habituation deficit. LacZ reporter expression in the brain reveals CerS6 expression in hippocampus, cortex, and the Purkinje cell layer of the cerebellum. Using newly developed antibodies that specifically recognize the CerS6 protein we show that the endogenous CerS6 protein is N-glycosylated and expressed in several tissues of mice, mainly kidney, small and large intestine, and brain.
authors.affiliation: From the Molecular Genetics, Life and Medical Sciences Institute (LIMES).
authors.forename: Philipp
authors.initials: P
authors.lastname: Ebel
authors.affiliation: Institute of Molecular Physiology and Biotechnology of Plants, and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Vom Dorp
authors.affiliation: the Department of Neuroanatomy and Molecular Brain Research, Ruhr-University of Bochum, 44801 Bochum, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petrasch-Parwez
authors.affiliation: the Mental Health Research and Treatment Center, Ruhr-University of Bochum, 44780 Bochum, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Zlomuzica
authors.affiliation: the Hôpital Charles Foix, Institut de la longévité, Paris 94205, France,; the Université Pierre et Marie Curie, Neurobiologie des Processus Adaptatifs, Paris 75005, France, and.
authors.forename: Kiyoka
authors.initials: K
authors.lastname: Kinugawa
authors.affiliation: the Hôpital Charles Foix, Institut de la longévité, Paris 94205, France,; the Université Pierre et Marie Curie, Neurobiologie des Processus Adaptatifs, Paris 75005, France, and.
authors.forename: Jean
authors.initials: J
authors.lastname: Mariani
authors.affiliation: From the Molecular Genetics, Life and Medical Sciences Institute (LIMES).
authors.forename: David
authors.initials: D
authors.lastname: Minich
authors.affiliation: From the Molecular Genetics, Life and Medical Sciences Institute (LIMES).
authors.forename: Christina
authors.initials: C
authors.lastname: Ginkel
authors.affiliation: the Department of Neuroscience, Max-Delbrueck-Centrum, Berlin, 13125 Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Welcker
authors.affiliation: From the Molecular Genetics, Life and Medical Sciences Institute (LIMES).
authors.forename: Joachim
authors.initials: J
authors.lastname: Degen
authors.affiliation: the Institute of Biochemistry and Molecular Biology, University of Bonn, 53115 Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eckhardt
authors.affiliation: the Mental Health Research and Treatment Center, Ruhr-University of Bochum, 44780 Bochum, Germany,; the Hôpital Charles Foix, Institut de la longévité, Paris 94205, France,; the Université Pierre et Marie Curie, Neurobiologie des Processus Adaptatifs, Paris 75005, France, and.
authors.forename: Ekrem
authors.initials: E
authors.lastname: Dere
authors.affiliation: Institute of Molecular Physiology and Biotechnology of Plants, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Dörmann
authors.affiliation: From the Molecular Genetics, Life and Medical Sciences Institute (LIMES),. Electronic address: k.willecke@uni-bonn.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Willecke
mesh_terms: D000818:Animals; D001007:Anxiety / Q000473:pathology / Q000503:physiopathology; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D057075:Enzyme Assays; D005106:Exploratory Behavior; D005455:Fluorescent Antibody Technique; D006031:Glycosylation; D057809:HEK293 Cells; D006185:Habituation, Psychophysiologic; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013058:Mass Spectrometry; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D010641:Phenotype; D013107:Sphingolipids / Q000737:chemistry / Q000378:metabolism*; D051049:Sphingosine N-Acyltransferase / Q000172:deficiency / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D013107:Sphingolipids; C584439:CERS6 protein, mouse; D051049:Sphingosine N-Acyltransferase; D001616:beta-Galactosidase
keywords: Brain; CerS6; Ceramide; Ceramide Synthase Activity; Glycerophospholipid; Kidney; Lass6; Mass Spectrometry (MS); Sphingomyelin