title: [Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth].
abstract: OBJECTIVE
  Gangliosides, i. e. sialic acid containing glycosphingolipids, constitute a major component of neuronal cells and are thought to be essential for brain function. UDP-glucose: ceramide glucosyl-transferase (Ugcg) catalyzes the initial step of glycosphingolipid (GSL) biosynthesis. A total deletion of the Ugcg-gene in mice led to embryonic lethality. In order to gain insight into the role of gangliosides in brain development and function, a cell specific disruption of Ugcg was performed.
  
  
  METHODS
  A cell specific disruption of Ugcg in mice was performed using the Cre/loxP-system. LoxP-flanked Ugcg-mice were generated and crossed with nestin-cre mice.
  
  
  RESULTS
  The nestin-promoted gene deletion in neuronal cells was indicated by the absence of virtually all gangliosides already at stage E15.5. Shortly after birth mice showed dysfunction of cerebellum and peripheral nerves, associated with structural defects. Axon-branching of Purkinje cells was significantly reduced. In primary cultures of neurons dendritic complexity was clearly diminished, while pruning occurred. Myelin sheaths of peripheral nerves were broadened and focally severely disorganized. GSL deficiency also led to a downregulation of gene expression sets involved in brain development and homeostasis. Mice died approximately 3 weeks after birth.
  
  
  CONCLUSIONS
  The pronounced neurologic symptoms in postnatal mice with neuronal specific deficiency of glucosylceramide synthesis demonstrate that GlcCer-derived GSL may not serve functions essential for early brain development. They are, however, required for neuron differentiation and brain maturation.
authors.affiliation: Zelluläre und Molekulare Pathologie, Deutsches Krebsforschungszentrum, Heidelberg.
authors.forename: R
authors.initials: R
authors.lastname: Jennemann
authors.forename: R
authors.initials: R
authors.lastname: Sandhoff
authors.forename: H
authors.initials: H
authors.lastname: Wiegandt
authors.forename: H-J
authors.initials: HJ
authors.lastname: Gröne
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D002531:Cerebellum / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D005964:Glucosyltransferases / Q000172:deficiency* / Q000235:genetics; D006028:Glycosphingolipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009436:Neural Tube Defects / Q000235:genetics*; D009474:Neurons / Q000473:pathology; D017933:Peripheral Nervous System / Q000473:pathology; D011247:Pregnancy; D011689:Purkinje Cells / Q000473:pathology
chemical_list: D006028:Glycosphingolipids; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase