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J. Biol. Chem., Vol. 282, Issue 22, 16700-16711, June 1, 2007

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Down-regulation of Polysialic Acid Is Required for Efficient Myelin Formation^*

Simon Ngamli Fewou¹, Hariharasubramanian Ramakrishnan¹, Heinrich Büssow, Volkmar Gieselmann, and Matthias Eckhardt²

From the Institute of Physiological Chemistry and Institute of Anatomy, University of Bonn, D-53115 Bonn, Germany

Oligodendrocyte precursor cells modify the neural cell adhesion molecule (NCAM) by the attachment of polysialic acid (PSA). Upon further differentiation into mature myelinating oligodendrocytes, however, oligodendrocyte precursor cells down-regulate PSA synthesis. In order to address the question of whether this down-regulation is a necessary prerequisite for the myelination process, transgenic mice expressing the polysialyltransferase ST8SiaIV under the control of the proteolipid protein promoter were generated. In these mice, postnatal down-regulation of PSA in oligodendrocytes was abolished. Most NCAM-120, the characteristic NCAM isoform in oligodendrocytes, carried PSA in the transgenic mice at all stages of postnatal development. Polysialylated NCAM-120 partially co-localized with myelin basic protein and was present in purified myelin. The permanent expression of PSA-NCAM in oligodendrocytes led to a reduced myelin content in the forebrains of transgenic mice during the period of active myelination and in the adult animal. In situ hybridizations indicated a significant decrease in the number of mature oligodendrocytes in the forebrain. Thus, down-regulation of PSA during oligodendrocyte differentiation is a prerequisite for efficient myelination by mature oligodendrocytes. Furthermore, myelin of transgenic mice exhibited structural abnormalities like redundant myelin and axonal degeneration, indicating that the down-regulation of PSA is also necessary for myelin maintenance.

Received for publication, November 21, 2006 , and in revised form, February 27, 2007.

^* This work was supported by the Deutsche Forschungsgemeinschaft. 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 The first two authors contributed equally to this work.

² To whom correspondence should be addressed: Institut für Physiologische Chemie, Rheinische Friedrich-Wilhelms-Universität Bonn, Nussallee 11, D-53115 Bonn, Germany. Tel.: 49-228-73-4735; Fax: 49-228-73-2416; E-mail: eckhardt{at}institut.physiochem.uni-bonn.de.

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