Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes.
Ceramide synthase 1 (CerS1) catalyzes the synthesis of C18 ceramide and is mainly expressed in the brain. Custom-made antibodies to a peptide from the C-terminal region of the mouse CerS1 protein yielded specific immunosignals in neurons but no other cell types of wild type brain, but the CerS1 protein was not detected in CerS1-deficient mouse brains. To elucidate the biological function of CerS1-derived sphingolipids in the brain, we generated CerS1-deficient mice by introducing a targeted mutation into the coding region of the cers1 gene. General deficiency of CerS1 in mice caused a foliation defect, progressive shrinkage, and neuronal apoptosis in the cerebellum. Mass spectrometric analyses revealed up to 60% decreased levels of gangliosides in cerebellum and forebrain. Expression of myelin-associated glycoprotein was also decreased by about 60% in cerebellum and forebrain, suggesting that interaction and stabilization of oligodendrocytic myelin-associated glycoprotein by neuronal gangliosides is due to the C18 acyl membrane anchor of CerS1-derived precursor ceramides. A behavioral analysis of CerS1-deficient mice yielded functional deficits including impaired exploration of novel objects, locomotion, and motor coordination. Our results reveal an essential function of CerS1-derived ceramide in the regulation of cerebellar development and neurodevelopmentally regulated behavior.
Molecular Genetics, University of Bonn, 53115 Bonn, Germany.
Christina
C
Ginkel
Dieter
D
Hartmann
Katharina
K
vom Dorp
Armin
A
Zlomuzica
Hany
H
Farwanah
Matthias
M
Eckhardt
Roger
R
Sandhoff
Joachim
J
Degen
Mariona
M
Rabionet
Ekrem
E
Dere
Peter
P
Dörmann
Konrad
K
Sandhoff
Klaus
K
Willecke
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D002518:Ceramides / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D005732:Gangliosides / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D018992:Myelin-Associated Glycoprotein / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology
D002518:Ceramides; D005732:Gangliosides; C104739:Mag protein, mouse; D018992:Myelin-Associated Glycoprotein; D010088:Oxidoreductases; C108138:dihydroceramide desaturase