title: Polysialic acid enters the cell nucleus attached to a fragment of the neural cell adhesion molecule NCAM to regulate the circadian rhythm in mouse brain.
abstract: In the mammalian nervous system, the neural cell adhesion molecule NCAM is the major carrier of the glycan polymer polysialic acid (PSA) which confers important functions to NCAM's protein backbone. PSA attached to NCAM contributes not only to cell migration, neuritogenesis, synaptic plasticity, and behavior, but also to regulation of the circadian rhythm by yet unknown molecular mechanisms. Here, we show that a PSA-carrying transmembrane NCAM fragment enters the nucleus after stimulation of cultured neurons with surrogate NCAM ligands, a phenomenon that depends on the circadian rhythm. Enhanced nuclear import of the PSA-carrying NCAM fragment is associated with altered expression of clock-related genes, as shown by analysis of cultured neuronal cells deprived of PSA by specific enzymatic removal. In vivo, levels of nuclear PSA in different mouse brain regions depend on the circadian rhythm and clock-related gene expression in suprachiasmatic nucleus and cerebellum is affected by the presence of PSA-carrying NCAM in the cell nucleus. Our conceptually novel observations reveal that PSA attached to a transmembrane proteolytic NCAM fragment containing part of the extracellular domain enters the cell nucleus, where PSA-carrying NCAM contributes to the regulation of clock-related gene expression and of the circadian rhythm.
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Westphal
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kleene
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany; Institut für Strukturelle Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Lutz
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Theis
authors.affiliation: Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA; Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou, Guangdong 515041, China. Electronic address: schachner@stu.edu.cn.
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002940:Circadian Rhythm; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D011485:Protein Binding; D012794:Sialic Acids / Q000378:metabolism*
chemical_list: D019006:Neural Cell Adhesion Molecules; D012794:Sialic Acids; C021319:polysialic acid
keywords: Circadian rhythm; NCAM; Nuclear import; Polysialic acid