title: Genetic ablation of polysialic acid causes severe neurodevelopmental defects rescued by deletion of the neural cell adhesion molecule.
abstract: Poly-alpha2,8-sialic acid (polySia) is a unique modification of the neural cell adhesion molecule, NCAM, tightly associated with neural development and plasticity. However, the vital role attributed to this carbohydrate polymer has been challenged by the mild phenotype of mice lacking polySia due to NCAM-deficiency. To dissect polySia and NCAM functions, we generated polySia-negative but NCAM-positive mice by simultaneous deletion of the two polysialyltransferase genes, St8sia-II and St8sia-IV. Beyond features shared with NCAM-null animals, a severe phenotype with specific brain wiring defects, progressive hydrocephalus, postnatal growth retardation, and precocious death was observed. These drastic defects were selectively rescued by additional deletion of NCAM, demonstrating that they originate from a gain of NCAM functions because of polySia deficiency. The data presented in this study reveal that the essential role of polySia resides in the control and coordination of NCAM interactions during mouse brain development. Moreover, this first demonstration in vivo that a highly specific glycan structure is more important than the glycoconjugate as a whole provides a novel view on the relevance of protein glycosylation for the complex process of building the vertebrate brain.
authors.affiliation: Zelluläre Chemie, Zentrum Biochemie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Weinhold
authors.forename: Ralph
authors.initials: R
authors.lastname: Seidenfaden
authors.forename: Iris
authors.initials: I
authors.lastname: Röckle
authors.forename: Martina
authors.initials: M
authors.lastname: Mühlenhoff
authors.forename: Frank
authors.initials: F
authors.lastname: Schertzinger
authors.forename: Sidonie
authors.initials: S
authors.lastname: Conzelmann
authors.forename: Jamey D
authors.initials: JD
authors.lastname: Marth
authors.forename: Rita
authors.initials: R
authors.lastname: Gerardy-Schahn
authors.forename: Herbert
authors.initials: H
authors.lastname: Hildebrandt
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism; D017353:Gene Deletion; D006031:Glycosylation; D006624:Hippocampus / Q000378:metabolism; D006849:Hydrocephalus / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008953:Models, Anatomic; D008954:Models, Biological; D009154:Mutation; D019006:Neural Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009830:Olfactory Bulb / Q000473:pathology; D010641:Phenotype; D011134:Polysaccharides / Q000737:chemistry; D012794:Sialic Acids / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors
chemical_list: D015815:Cell Adhesion Molecules; D019006:Neural Cell Adhesion Molecules; D011134:Polysaccharides; D012794:Sialic Acids; C021319:polysialic acid