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* Department of Cell Biology, We have investigated the potential role of
contactin and contactin-associated protein (Caspr) in
the axonal-glial interactions of myelination. In the nervous system, contactin is expressed by neurons, oligodendrocytes, and their progenitors, but not by Schwann
cells. Expression of Caspr, a homologue of Neurexin
IV, is restricted to neurons. Both contactin and Caspr
are uniformly expressed at high levels on the surface of
unensheathed neurites and are downregulated during
myelination in vitro and in vivo. Contactin is downregulated along the entire myelinated nerve fiber. In contrast, Caspr expression initially remains elevated along segments of neurites associated with nascent myelin
sheaths. With further maturation, Caspr is downregulated in the internode and becomes strikingly concentrated in the paranodal regions of the axon, suggesting
that it redistributes from the internode to these sites.
Caspr expression is similarly restricted to the paranodes of mature myelinated axons in the peripheral
and central nervous systems; it is more diffusely and
persistently expressed in gray matter and on unmyelinated axons. Immunoelectron microscopy demonstrated that Caspr is localized to the septate-like junctions that form between axons and the paranodal loops
of myelinating cells. Caspr is poorly extracted by nonionic detergents, suggesting that it is associated with the
axon cytoskeleton at these junctions. These results indicate that contactin and Caspr function independently during myelination and that their expression is regulated by glial ensheathment. They strongly implicate
Caspr as a major transmembrane component of the
paranodal junctions, whose molecular composition has
previously been unknown, and suggest its role in the reciprocal signaling between axons and glia.
Department of Neurology, § The Kaplan Cancer Center, New York University Medical School,
New York 10016; Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; ¶ Department of Neurology and Neuroscience, Division of Neurobiology, Cornell University Medical College, New York 10021;
and ** Sugen, Inc., Redwood City, California 94063
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