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J. Biol. Chem., Vol. 280, Issue 52, 42971-42977, December 30, 2005

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Genetic Ablation of Polysialic Acid Causes Severe Neurodevelopmental Defects Rescued by Deletion of the Neural Cell Adhesion Molecule^*

Birgit Weinhold, Ralph Seidenfaden1, Iris Röckle, Martina Mühlenhoff, Frank Schertzinger, Sidonie Conzelmann, Jamey D. Marth¶, Rita Gerardy-Schahn2, and Herbert Hildebrandt

From the Zelluläre Chemie, Zentrum Biochemie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany, Institut für Zoologie (220), Universität Hohenheim, Garbenstrasse 30, 70593 Stuttgart, Germany, and ^¶Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093

Poly-2,8-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.

Received for publication, October 12, 2005

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft (to R. G.-S., H. H., and M. M.), National Institutes of Health (to J. D. M.), the Fonds der Chemischen Industrie (to R. G.-S.), and the Deutsche Krebshilfe (to M. M. and H. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Institut de Biologie du Développement de Marseille, Campus de Luminy, 13288 Marseille 9, France.

² To whom correspondence should be addressed. Tel.: 49-511-532-9802; Fax: 49-511-532-8801; E-mail: Gerardy-schahn.rita{at}mh-hannover.de.

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