title: Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth.
abstract: Sialic acid-containing glycosphingolipids, i.e., gangliosides, constitute a major component of neuronal cells and are thought to be essential for brain function. UDP-glucose:ceramide glucosyltransferase (Ugcg) catalyzes the initial step of glycosphingolipid (GSL) biosynthesis. To gain insight into the role of GSLs in brain development and function, a cell-specific disruption of Ugcg was performed as indicated by the absence of virtually all glucosylceramide-based GSLs. 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, and pruning occurred early. Myelin sheaths of peripheral nerves were broadened and focally severely disorganized. GSL deficiency also led to a down-regulation of gene expression sets involved in brain development and homeostasis. Mice died approximately 3 weeks after birth. These results imply that GSLs are essential for brain maturation.
authors.affiliation: Abteilungen Zelluläre und Molekulare Pathologie, Deutsches Krebsforschungszentrum Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. r.jennemann@dkfz.de
authors.forename: Richard
authors.initials: R
authors.lastname: Jennemann
authors.forename: Roger
authors.initials: R
authors.lastname: Sandhoff
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.forename: Eva
authors.initials: E
authors.lastname: Kiss
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Cecilia
authors.initials: C
authors.lastname: Zuliani
authors.forename: Ana
authors.initials: A
authors.lastname: Martin-Villalba
authors.forename: Richard
authors.initials: R
authors.lastname: Jäger
authors.forename: Hubert
authors.initials: H
authors.lastname: Schorle
authors.forename: Marc
authors.initials: M
authors.lastname: Kenzelmann
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Bonrouhi
authors.forename: Herbert
authors.initials: H
authors.lastname: Wiegandt
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D018390:Gene Targeting; D005964:Glucosyltransferases / Q000172:deficiency* / Q000235:genetics; D006028:Glycosphingolipids / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D006028:Glycosphingolipids; D012333:RNA, Messenger; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase