title: Glycosphingolipid synthesis in cerebellar Purkinje neurons: roles in myelin formation and axonal homeostasis.
abstract: Glycosphingolipids (GSLs) occur in all mammalian plasma membranes. They are most abundant in neuronal cells and have essential roles in brain development. Glucosylceramide (GlcCer) synthase, which is encoded by the Ugcg gene, is the key enzyme driving the synthesis of most neuronal GSLs. Experiments using conditional Nestin-Cre Ugcg knockout mice have shown that GSL synthesis in vivo is essential, especially for brain maturation. However, the roles of GSL synthesis in mature neurons remain elusive, since Nestin-Cre is expressed in neural precursors as well as in postmitotic neurons. To address this problem, we generated Purkinje cell-specific Ugcg knockout mice using mice that express Cre under the control of the L7 promoter. In these mice, Purkinje cells survived for at least 10-18 weeks after Ugcg deletion. We observed apparent axonal degeneration characterized by the accumulation of axonal transport cargos and aberrant membrane structures. Dendrites, however, were not affected. In addition, loss of GSLs disrupted myelin sheaths, which were characterized by detached paranodal loops. Notably, we observed doubly myelinated axons enveloped by an additional concentric myelin sheath around the original sheath. Our data show that axonal GlcCer-based GSLs are essential for axonal homeostasis and correct myelin sheath formation.
authors.affiliation: Laboratory for Molecular Membrane Neuroscience, Brain Science Institute, RIKEN, Wako-Shi, Saitama, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Watanabe
authors.forename: Shogo
authors.initials: S
authors.lastname: Endo
authors.forename: Eriko
authors.initials: E
authors.lastname: Oshima
authors.forename: Tomiko
authors.initials: T
authors.lastname: Hoshi
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Higashi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yamada
authors.forename: Koujiro
authors.initials: K
authors.lastname: Tohyama
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirabayashi
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002531:Cerebellum / Q000378:metabolism / Q000648:ultrastructure; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism*; D006028:Glycosphingolipids / Q000096:biosynthesis / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D011689:Purkinje Cells / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D006028:Glycosphingolipids; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase