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Acid and neutral sphingomyelinases, structures, functions and molecular biology

The role of acid (SMPD-1) and neutral sphingomyelinases (SMPD-2 and SMPD-3)

Sphingomyelins are main constituents of all eukaryotic membrane lipid bilayers with structural functions and as precursor molecule of a variety of cell signalling molecules. To get further insight into the role of sphingomyelin and acid and neutral sphingomyelinases we have chosen the loss of structure - loss of function genetic approach and generated the acid sphingomyelin mouse model (smpd1-/-) and characterized as a mimicry of the human Niemann-Pick disease, type A.

To undertand the so far unknown role of neutral sphingomyelinases in cellular metabolism and particularly with respect to their proposed role as key players in apoptotic signalling pathways we succeeded in the last funding period in cloning the ubiquitously occurring neutral sphingomyelinase 1 (smpd2) and the mainly in CNS expressed smpd3 and generated subsequently the respective null allelic mouse mutant models smpd2-/-, smpd3-/- and by crossing the two genotype also the smpd2-/-smpd3-/- double mutant, which proved to be free of any Mg++ dependent neutral sphingomyelinase activity.

The smpd3-/- and smpd2-/-smpd3-/- double mutant show an surprizing dwarf phenotype, which bases on a general postnatal growth retardation, due to hypoplasia not apoptosis. We have identified the hypothalamic GHRH secreting neurosecretory neurons as check point.

SMPD3 plays a key role in postnatal development.
Our biochemical and cell biological analytical data suggested that postnatal the Golgi residing SMPD3 is the regulating element in the GHRH ( and possibly other peptide hormones)-secretory Golgi pathway. The molecular analysis of the cellular processes (SMPD3 and vesicle formation and trafficking has evolved now as a focus of this project.

Different from the lysosomal sphingomyelinase as "house keeping" enzyme SPMD3 is a regulated enzyme activity. We have isolated the promoter of the mainly brain expressed smpd3 in order a. to study the important role of cell specific and developmental regulation of smpd3 expression, and for rescue experiments of the dwarf phenotype in the smpd3-/- mouse with smpd3 specific cDNA under the control of the smpd3 and chondrocyte specific promoters.


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Figure 1: smpd3-/- develop a chondrodysplastic dwarfism. Comparison of size, weight and organ size of age matched wt- and smdp3 -/- mice.


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Figure 2: Chondrodysplasia in smdp3-/- adult mice.


References
  1. Stoffel W, Jenke B, Holz B, Binczek E, Günter RH, Knifka J, Koebke J, Niehoff A. Neutral sphingomyelinase (SMPD3) deficiency causes a novel form of chondrodysplasia and dwarfism that is rescued by Col2A1-driven smpd3 transgene expression. Am J Pathol. 2007 Jul;171(1):153-61.
  2. Stoffel W, Jenke B, Holz B, Binczek E, Günter RH, Knifka J, Koebke J, Niehoff A.Neutral Sphingomyelinase (SMPD3) Deficiency Causes a Novel Form of Chondrodysplasia and Dwarfism That Is Rescued by Col2A1-Driven smpd3 Transgene Expression. Am J Pathol. 2007 Apr 26; [Epub ahead of print]
  3. Binczek E, Jenke B, Holz B, Günter RH, Thevis M, Stoffel W. Obesity resistance of the stearoyl-CoA desaturase-deficient (scd1-/-) mouse results from disruption of the epidermal lipid barrier and adaptive thermoregulation. Biol Chem. 2007 Apr;388(4):405-18.
  4. Stoffel W, Jenke B, Blöck B, Zumbansen M, Koebke J. Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and development. Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4554-9.
  5. Stoffel, W., Jenke, B., Blöck, B., Zumbansen, M., and Koebke, J. (2004). Brain Specific Neutral Sphingomyelinase (smpd3) is a key factor in growth regulation, submitted to Cell.
  6. Zumbansen, M., and Stoffel, W. (2002). Neutral sphingomyelinase 1 deficiency in the mouse causes no lipid storage disease, Mol. Cell Biol. 22, 3633-3638
  7. Nix, M. and Stoffel, W. (2000) Perturbation of membrane microdomains reduces mitogenic signaling and increases susceptibility to apoptosis after T cell receptor stimulation Cell Death and Differentiation 7, 413-424
  8. Tomiuk, S., Zumbansen, M., and Stoffel, W. (2000) Characterization and Subcellular Localization of Murine and Human Magnesium-dependent Neutral Sphingomyelinase J. Biol. Chemistry 275, 5710-5717
  9. Hofmann, K., Tomiuk, S, Wolff, G. and Stoffel, W. 2000 Cloning and characterization of the mammalian brain-specific, Mg2+-dependent neutral sphingomyelinase Proc. Natl. Acad. Sci. USA 97, 5895-5900
  10. Stoffel, B., Bauer, P. Nix, M., Deres, K. And Stoffel, W. (1998) Ceramide-independent CD28 and TCR signaling but reduced IL-2 secretion in T cells of acid sphingomyelinase-deficient mice Eur. J. Immunol. 28, 874-880
  11. Tomiuk, S., Hofmann, K., Nix, M., Zumbansen, M. and Wilhelm Stoffel (1998) Cloned mammalian neutral sphingomyelinase: Functions in sphingolipid signaling? Proc.Natl.Acad. Sci.USA 95, 3638-3643
  12. Kümmel, T.A., Thiele, J., Schroeder, R. and Stoffel, W. (1997) Pathology of Visceral Organs and Bone Marrow in an Acid Sphingomyelinase Deficient Knock-Out Mouse Line, Mimicking Human Niemann-Pick Disease Type A. A Light and Electron Microscopic Study Pathology Research and Practice 193, 663-671
  13. Zumbansen, M. and Stoffel, W. (1997). Tumor Necrosis Factor a Activates NF-kB in Acid Sphingomyelinase-deficient Mouse Embryonic Fibroblasts. J.Biol.Chem. 272, 10904-10909.
  14. Kümmel, Th.A., Schroeder, R. and Stoffel, W. (1997) Light and Electron Microscopic Analysis of the Central and Peripheral Nervous Systems of Acid Sphingomyelinase-Deficient Mice Resulting from Gene Targeting Journal of Neuropathology and Experimental Neurology 56, 171-179
  15. Newrzella, D. and Stoffel, W. (1996) Functional Analysis of the Glycosylation of Murine Acid Sphingomyelinase J. Biol.Chem. 271, 32089-32095.
  16. B. Otterbach, W. Stoffel (1995) Acid sphingomyelinase-deficient mice mimic the neurovisceral form of human lysosomal storage disease (Niemann-Pick disease) Cell 81, 1053-1061
  17. D. Newrzella, W. Stoffel (1992) Molecular cloning of the acid sphingomyelinase of the mouse and the organization and complete nucleotide sequence of the gene. Biol. Chem. Hoppe-Seyler, 373, 1233-1238


July 12, 2011
Center for Biochemistry, Joseph-Stelzmann-Straße 52, D50931 Cologne
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