Inactivation of ceramide synthase 6 in mice results in an altered sphingolipid metabolism and behavioral abnormalities

Journal of Biological Chemistry

Volumn 288, Issue 29, 2013, Pages 21433-21447

  Ebel, Philipp ^a   Vom Dorp, Katharina ^a   Petrasch Parwez, Elisabeth ^b   Zlomuzica, Armin ^b   Kinugawa, Kiyoka ^c,d   Mariani, Jean ^c,d   Minich, David ^a   Ginkel, Christina ^a   Welcker, Jochen ^e   Degen, Joachim ^a   Eckhardt, Matthias ^a   Dere, Ekrem ^b,c,d   Dörmann, Peter ^a   Willecke, Klaus ^a  

^a UNIVERSITY OF BONN   (Germany)

^b RUHR UNIVERSITY BOCHUM   (Germany)

^c HÔPITAL CHARLES FOIX   (France)

^d SORBONNE UNIVERSITÉ   (France)

^e MAX DELBRÜCK CENTER FOR MOLECULAR MEDICINE   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CERAMIDE SYNTHASE; SPHINGOLIPID METABOLISM; SPHINGOLIPIDS; SPHINGOSINE; SYNTHASES;

CERAMIDES; METABOLISM; PHYSIOLOGY;

MAMMALS;

CERAMIDE DERIVATIVE; CERAMIDE SYNTHASE 6; SPHINGOLIPID; UNCLASSIFIED DRUG;

ACYLATION; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTIBODY SPECIFICITY; ARTICLE; BEHAVIOR DISORDER; BRAIN CORTEX; CATALYSIS; CERAMIDE SYNTHASE 6 GENE; CONTROLLED STUDY; GENE; GENE INACTIVATION; GLYCOSYLATION; HABITUATION; HETEROZYGOSITY; HIPPOCAMPUS; HOMEOSTASIS; LACZ GENE; LIPOGENESIS; MALE; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN DOMAIN; PROTEIN EXPRESSION; PURKINJE CELL; THIN LAYER CHROMATOGRAPHY; TIME OF FLIGHT MASS SPECTROMETRY; TISSUE DISTRIBUTION;

BRAIN; CERAMIDE; CERAMIDE SYNTHASE ACTIVITY; CERS6; GLYCEROPHOSPHOLIPID; KIDNEY; LASS6; MASS SPECTROMETRY (MS); SPHINGOMYELIN;

ANIMALS; ANXIETY; BEHAVIOR, ANIMAL; BETA-GALACTOSIDASE; BRAIN; ENZYME ACTIVATION; ENZYME ASSAYS; EXPLORATORY BEHAVIOR; FLUORESCENT ANTIBODY TECHNIQUE; GLYCOSYLATION; HABITUATION, PSYCHOPHYSIOLOGIC; HEK293 CELLS; HUMANS; KIDNEY GLOMERULUS; MASS SPECTROMETRY; MAZE LEARNING; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; ORGAN SPECIFICITY; PHENOTYPE; SPHINGOLIPIDS; SPHINGOSINE N-ACYLTRANSFERASE;

EID: 84880518566     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M113.479907     Document Type: Article

References (51)

1. Hannun, Y. A., and Obeid, L. M. (2008) Principles of bioactive lipid signalling. Lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 9,139-150
2. Kitatani, K., Idkowiak-Baldys, J., and Hannun, Y. A. (2008) The sphingo-lipid salvage pathway in ceramide metabolism and signaling. Cell. Signal. 20,1010-1018
3. Haimovitz-Friedman, A., Kan, C. C., Ehleiter, D., Persaud, R. S., McLough-lin, M., Fuks, Z., and Kolesnick, R. N. (1994) Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J. Exp. Med. 180, 525-535
4. van Echten, G., and Sandhoff, K. (1993) Ganglioside metabolism. Enzy-mology, topology, and regulation. J. Biol. Chem. 268, 5341-5344
5. Stiban, J., Tidhar, R., and Futerman, A. H. (2010) Ceramide synthases. Roles in cell physiology and signaling. Adv. Exp. Med. Biol. 688, 60-71
6. Mizutani, Y., Kihara, A., and Igarashi, Y. (2005) Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem. J. 390, 263-271
7. Laviad, E. L., Albee, L., Pankova-Kholmyansky, I., Epstein, S., Park, H., Merrill, A. H., Jr., and Futerman, A. H. (2008) Characterization of cer-amide synthase 2. Tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J. Biol. Chem. 283, 5677-5684
8. Winter, E., and Ponting, C. P. (2002) TRAM, LAG1 and CLN8. Members of a novel family of lipid-sensing domains? Trends Biochem. Sci. 27, 381-383
9. Tidhar, R., Ben-Dor, S., Wang, E., Kelly, S., Merrill, A. H., Jr., and Futer-man, A. H. (2012) Acyl chain specificity of ceramide synthases is determined within a region of 150 residues in the Tram-Lag-CLN8 (TLC) do-main. J. Biol. Chem. 287, 3197-3206
10. Spassieva, S., Seo, J. G., Jiang, J. C., Bielawski, J., Alvarez-Vasquez, F., Jaz-winski, S. M., Hannun, Y. A., and Obeid, L. M. (2006) Necessary role for the Laglp motif in (dihydro)ceramide synthase activity. J. Biol. Chem. 281, 33931-33938
11. Venkataraman, K., and Futerman, A. H. (2002) Do longevity assurance genes containing Hox domains regulate cell development via ceramide synthesis? FEBSLett. 528, 3-4
12. Lee, S. J. (1991) Expression of growth/differentiation factor 1 in the nervous system: conservation of a bicistronic structure. Proc. Natl. Acad. Sci. U.S.A. 88, 4250-4254
13. Zhao, L., Spassieva, S. D., Jucius, T. J., Shultz, L. D., Shick, H. E., Macklin, W. B., Hannun, Y. A., Obeid, L. M., and Ackerman, S. L. (2011) A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation. PLoS Genet. 7, e1002063
14. Ginkel, C., Hartmann, D., Vom Dorp, K., Zlomuzica, A., Farwanah, H., Eckhardt, M., Sandhoff, R., Degen, J., Rabionet, M., Dere, E., Doermann, P., Sandhoff, K., and Willecke, K. (2012) Ablation of neuronal ceramide syn-thase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes. J. Biol. Chem. 287, 41888-41902
15. Imgrund, S., Hartmann, D., Farwanah, H., Eckhardt, M., Sandhoff, R., Degen, J., Gieselmann, V., Sandhoff, K., and Willecke, K. (2009) Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J. Biol. Chem. 284, 33549-33560
16. Pewzner-Jung, Y., Park, H., Laviad, E. L., Silva, L. C., Lahiri, S., Stiban, J., Erez-Roman, R., Brugger, B., Sachsenheimer, T., Wieland, F., Prieto, M., Merrill, A. H., Jr., and Futerman, A. H. (2010) A critical role for ceramide synthase 2 in liver homeostasis. I. Alterations in lipid metabolic pathways. J. Biol. Chem. 285, 10902-10910
17. Pewzner-Jung, Y., Brenner, O., Braun, S., Laviad, E. L., Ben-Dor, S., Feldmesser, E., Horn-Saban, S., Amann-Zalcenstein, D., Raanan, C., Ber-kutzki, T., Erez-Roman, R., Ben-David, O., Levy, M., Holzman, D., Park, H., Nyska, A., Merrill, A. H., Jr., and Futerman, A. H. (2010) A critical role for ceramide synthase 2 in liver homeostasis. II. Insights into molecular changes leading to hepatopathy. J. Biol. Chem. 285,10911-10923
18. Mizutani, Y., Kihara, A., and Igarashi, Y. (2006) LASS3 (longevity assurance homologue 3) is a mainly testis-specific (dihydro)ceramide synthase with relatively broad substrate specificity. Biochem. J. 398, 531-538
19. Jennemann, R., Rabionet, M., Gorgas, K., Epstein, S., Dalpke, A., Rother-mel, U., Bayerle, A., van der Hoeven, F., Imgrund, S., Kirsch, J., Nickel, W., Willecke, K., Riezman, H., Grone, H. J., and Sandhoff, R. (2012) Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum. Mol. Genet. 21, 586-608
20. Levy, M., and Futerman, A. H. (2010) Mammalian ceramide synthases. IUBMB Life 62, 347-356
21. Schiffmann, S., Ferreiros, N., Birod, K., Eberle, M., Schreiber, Y., Pfeilschifter, W., Ziemann, U., Pierre, S., Scholich, K., Grosch, S., and Geisslinger, G. (2012) Ceramide synthase 6 plays a critical role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 188, 5723-5733
22. Senkal, C. E., Ponnusamy, S., Bielawski, J., Hannun, Y. A., and Ogretmen, B. (2010) Antiapoptotic roles ofceramide-synthase-6-generated C16-cer-amide via selective regulation of the ATF6/CHOP arm of ER-stress-re-sponse pathways. FASEB J. 24, 296-308
23. Gierl, M. S., Karoulias, N., Wende, H., Strehle, M., and Birchmeier, C. (2006) The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells. Genes Dev. 20, 2465-2478
24. Lee, E. C., Yu, D., Martinez de Velasco, J., Tessarollo, L., Swing, D. A., Court, D. L., Jenkins, N. A., and Copeland, N. G. (2001) A highly efficient Escherichia coli-based chromosome engineering system adapted for re-combinogenic targeting and subcloning of BAC DNA. Genomics 73, 56-65
25. Buchholz, F., Angrand, P. O., and Stewart, A. F. (1996) A simple assay to determine the functionality of Cre or FLP recombination targets in genomic manipulation constructs. Nucleic Acids Res. 24, 3118 -3119
26. Magin, T. M., McWhir, J., and Melton, D. W. (1992) A new mouse embryonic stem cell line with good germ line contribution and gene targeting frequency. Nucleic Acids Res. 20, 3795-3796
27. Wells, D. (1993) Production of chimeras derived from murine embryonic stem cells. Methods Mol. Biol. 18, 217-237
28. Requardt, R. P., Kaczmarczyk, L., Dublin, P., Wallraff-Beck, A., Mikeska, T., Degen, J., Waha, A., Steinhäuser, C., Willecke, K., and Theis, M. (2009) Quality control of astrocyte-directed Cre transgenic mice. The benefits of a direct link between loss of gene expression and reporter activation. Glia 57, 680-692
29. Kim, H. J., Qiao, Q., Toop, H. D., Morris, J. C., and Don, A. S. (2012) A fluorescent assay for ceramide synthase activity. J. Lipid Res. 53, 1701-1707
30. Petrasch-Parwez, E., Habbes, H. W., Weickert, S., Löbbecke- Schumacher, M., Striedinger, K., Wieczorek, S., Dermietzel, R., and Epplen, J. T. (2004) Fine-structural analysis and connexin expression in the retina of a transgenic model of Huntington's disease. J. Comp. Neurol. 479,181-197
31. Petrasch-Parwez, E., Nguyen, H. P., Löbbecke-Schumacher, M., Habbes, H. W., Wieczorek, S., Riess, O., Andres, K. H., Dermietzel, R., and Von Hörsten, S. (2007) Cellular and subcellular localization of Huntingtin (corrected) aggregates in the brain of a rat transgenic for Huntington disease. J. Comp. Neurol. 501, 716 -730
32. Welti, R., Li, W., Li, M., Sang, Y., Biesiada, H., Zhou, H. E., Rajashekar, C. B., Williams, T. D., and Wang, X. (2002) Profiling membrane lipids in plant stress responses. Role of phospholipase Da in freezing-induced lipid changes in Arabidopsis. J. Biol. Chem. 277, 31994-32002
33. Brügger, B., Erben, G., Sandhoff, R., Wieland, F. T., and Lehmann, W. D. (1997) Quantitative analysis of biological membrane lipids at the low pi-comole level by nano-electrospray ionization tandem mass spectrometry. Proc. Natl. Acad. Sci. U.S.A. 94, 2339 -2344
34. Wewer, V., Dombrink, I., vom Dorp, K., and Dörmann, P. (2011) Quantification of sterol lipids in plants by quadrupole time-of-flight mass spec-trometry. J. LipidRes. 52, 1039 -1054
35. Homma, D., Sumi-Ichinose, C., Tokuoka, H., Ikemoto, K., Nomura, T., Kondo, K., Katoh, S., and Ichinose, H. (2011) Partial biopterin deficiency disturbs postnatal development of the dopaminergic system in the brain. J. Biol. Chem. 286,1445-1452
36. Gantois, I., Fang, K., Jiang, L., Babovic, D., Lawrence, A. J., Ferreri, V., Teper, Y., Jupp, B., Ziebell, J., Morganti-Kossmann, C. M., O'Brien, T. J., Nally, R., Schütz, G., Waddington, J., Egan, G. F., and Drago, J. (2007) Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior. Proc. Natl. Acad. Sci. U.S.A. 104, 4182-4187
37. Zlomuzica, A., Tress, O., Binder, S., Rovira, C., Willecke, K., and Dere, E. (2012) Changes in object recognition and anxiety-like behaviour in mice expressing a cx47 mutation that causes pelizaeus-merzbacher-like disease. Dev. Neurosci. 34, 277-287
38. Dere, E., De Souza Silva, M. A., Topic, B., Fiorillo, C., Li, J. S., Sadile, A. G., Frisch, C., and Huston, J. P. (2002) Aged endothelial nitric-oxide synthase knockout mice exhibit higher mortality concomitant with impaired open-field habituation and alterations in forebrain neurotransmitter levels. Genes Brain Behav. 1, 204-213
39. Dere, E., Huston, J. P., and De Souza Silva, M. A. (2007) The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci. Biobehav. Rev. 31, 673-704
40. Dere, E., Topic, B., De Souza Silva, M. A., Srejic, M., Frisch, C., Budden-berg, T., and Huston, J. P. (2002) The graded anxiety test. A novel test of murine unconditioned anxiety based on the principles of the elevated plus-maze and light-dark test. J. Neurosci. Methods 122, 65-73
41. Becker, I., Wang-Eckhardt, L., Yaghootfam, A., Gieselmann, V., and Eckhardt, M. (2008) Differential expression of (dihydro)ceramide synthases in mouse brain. Oligodendrocyte-specific expression of CerS2/Lass2. His-tochem. Cell Biol. 129, 233-241
42. Rodriguez, A., Griffiths-Jones, S., Ashurst, J. L., and Bradley, A. (2004) Identification of mammalian microRNA host genes and transcription units. Genome Res. 14, 1902-1910
43. Grösch, S., Schiffmann, S., and Geisslinger, G. (2012) Chain length-specific properties of ceramides. Prog. Lipid Res. 51, 50-62
44. Thomas, R. L., Jr., Matsko, C. M., Lotze, M. T., and Amoscato, A. A. (1999) Mass spectrometric identification of increased C16 ceramide levels during apoptosis. J. Biol. Chem. 274, 30580-30588
45. Mullen, T. D., Spassieva, S., Jenkins, R. W., Kitatani, K., Bielawski, J., Han-nun, Y. A., and Obeid, L. M. (2011) Selective knockdown of ceramide synthases reveals complex interregulation of sphingolipid metabolism. J. Lipid Res. 52, 68 -77
46. Cuellar, T. L., Davis, T. H., Nelson, P. T., Loeb, G. B., Harfe, B. D., Ullian, E., and McManus, M. T. (2008) Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 105, 5614-5619
47. Yamashita, T., Allende, M. L., Kalkofen, D. N., Werth, N., Sandhoff, K., and Proia, R. L. (2005) Conditional LoxP-flanked glucosylceramide synthase allele controlling glycosphingolipid synthesis. Genesis 43, 175-180
48. Sun, Y., Witte, D. P., Ran, H., Zamzow, M., Barnes, S., Cheng, H., Han, X., Williams, M. T., Skelton, M. R., Vorhees, C. V., and Grabowski, G. A. (2008) Neurological deficits and glycosphingolipid accumulation in sapo-sin B deficient mice. Hum. Mol. Genet. 17, 2345-2356
49. O'Keefe, J., and Dostrovsky, J. (1971) The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res. 34, 171-175
50. Tabatadze, N., Savonenko, A., Song, H., Bandaru, V. V., Chu, M., and Haughey, N. J. (2010) Inhibition of neutral sphingomyelinase-2 perturbs brain sphingolipid balance and spatial memory in mice. J. Neurosci. Res. 88, 2940-2951
51. Wheeler, D., Bandaru, V. V., Calabresi, P. A., Nath, A., and Haughey, N. J. (2008) A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis. Brain 131, 3092-3102