title: Neutral sphingomyelinase (SMPD3) deficiency disrupts the Golgi secretory pathway and causes growth inhibition.
abstract: Systemic loss of neutral sphingomyelinase (SMPD3) in mice leads to a novel form of systemic, juvenile hypoplasia (dwarfism). SMPD3 deficiency in mainly two growth regulating cell types contributes to the phenotype, in chondrocytes of skeletal growth zones to skeletal malformation and chondrodysplasia, and in hypothalamic neurosecretory neurons to systemic hypothalamus-pituitary-somatotropic hypoplasia. The unbiased smpd3-/- mouse mutant and derived smpd3-/- primary chondrocytes were instrumental in defining the enigmatic role underlying the systemic and cell autonomous role of SMPD3 in the Golgi compartment. Here we describe the unprecedented role of SMPD3. SMPD3 deficiency disrupts homeostasis of sphingomyelin (SM), ceramide (Cer) and diacylglycerol (DAG) in the Golgi SMPD3-SMS1 (SM-synthase1) cycle. Cer and DAG, two fusogenic intermediates, modify the membrane lipid bilayer for the initiation of vesicle formation and transport. Dysproteostasis, unfolded protein response, endoplasmic reticulum stress and apoptosis perturb the Golgi secretory pathway in the smpd3-/- mouse. Secretion of extracellular matrix proteins is arrested in chondrocytes and causes skeletal malformation and chondrodysplasia. Similarly, retarded secretion of proteo-hormones in hypothalamic neurosecretory neurons leads to hypothalamus induced combined pituitary hormone deficiency. SMPD3 in the regulation of the protein vesicular secretory pathway may become a diagnostic target in the etiology of unknown forms of juvenile growth and developmental inhibition.
authors.affiliation: Center of Molecular Medicine (CMMC), Laboratory of Molecular Neurosciences, Center for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.|Cluster of Excellence, Cellular Stress Response in Aging-Related Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Stoffel
authors.affiliation: Center of Molecular Medicine (CMMC), Laboratory of Molecular Neurosciences, Center for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.|Cluster of Excellence, Cellular Stress Response in Aging-Related Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Hammels
authors.affiliation: Center of Molecular Medicine (CMMC), Laboratory of Molecular Neurosciences, Center for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.
authors.forename: Bitta
authors.initials: B
authors.lastname: Jenke
authors.affiliation: Cluster of Excellence, Cellular Stress Response in Aging-Related Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Erika
authors.initials: E
authors.lastname: Binczek
authors.affiliation: Center of Molecular Medicine (CMMC), Laboratory of Molecular Neurosciences, Center for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Schmidt-Soltau
authors.affiliation: Cluster of Excellence, Cellular Stress Response in Aging-Related Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Brodesser
authors.affiliation: Cluster of Excellence, Cellular Stress Response in Aging-Related Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Schauss
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Center for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Etich
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Center for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Heilig
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Center for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.|Dr Rolf M Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital, Friedrichsheim gGmbh, Frankfurt/Main, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Zaucke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D020869:Gene Expression Profiling; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism*; D057809:HEK293 Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D055571:Secretory Pathway / Q000187:drug effects; D012995:Solubility; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency* / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: C011439:1,2-diacylglycerol; D002518:Ceramides; D003902:Detergents; D004075:Diglycerides; D013109:Sphingomyelins; C556686:Sgms1 protein, mouse; D017855:Transferases (Other Substituted Phosphate Groups); D010738:Type C Phospholipases; C491483:Smpd3 protein, mouse; D013108:Sphingomyelin Phosphodiesterase