Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 12, 8412-8417, June 11, 2002

Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration
Alka A. Vyas*, Himatkumar V. Patel*, Susan E. Fromholt*, Marija Heffer-Lauc*, Kavita A. Vyas*, Jiyoung Dang*, Melitta Schachner, and Ronald L. Schnaar*,

*テつ*Departments of Pharmacology and Neuroscience, The Johns Hopkins School of Medicine, Baltimore, MD 21205; and テつ*Zentrum fuer Molekulare Neurobiologie, Universitaet Hamburg, D-20246 Hamburg, Germany

Communicated by Saul Roseman, The Johns Hopkins University, Baltimore, MD, April 7,テつ*2002 (received for review February 20,テつ*2002)

Myelin-associated glycoprotein (MAG) binds to the nerve cell surface and inhibits nerve regeneration. The nerve cell surface ligand(s) for MAG are not established, although sialic acid-bearing glycans have been implicated. We identify the nerve cell surface gangliosides GD1a and GT1b as specific functional ligands for MAG-mediated inhibition of neurite outgrowth from primary rat cerebellar granule neurons. MAG-mediated neurite outgrowth inhibition is attenuated by (i) neuraminidase treatment of the neurons; (ii) blocking neuronal ganglioside biosynthesis; (iii) genetically modifying the terminal structures of nerve cell surface gangliosides; and (iv) adding highly specific IgG-class antiganglioside mAbs. Furthermore, neurite outgrowth inhibition is mimicked by highly multivalent clustering of GD1a or GT1b by using precomplexed antiganglioside Abs. These data implicate the nerve cell surface gangliosides GD1a and GT1b as functional MAG ligands and suggest that the first step in MAG inhibition is multivalent ganglioside clustering.